Question:

How do cancer cells feed?

Answer:

Cancer doesn't feed. It is uncontrolled cell division, the molecular structure gets changed somehow.

More Info:


Cancer cell
Cancer cells are cells that grow and divide at an unregulated, quickened pace. Although cancer cells can be quite common in a person they are only malignant when the other cells (particularly natural killer cells) fail to recognize and/or destroy them. In the past a common belief was that cancer cells failed to be recognized and destroyed because of a weakness in the immune system. However, more recent research has shown that the failure to recognize cancer cells is caused by the lack of particular co-stimulated molecules that aid in the way antigens react with lymphocytes. By researching stem cells scientists have suggested that too much SP2 protein may turn stem cells into cancer cells. Other issues thought to play a role in the spread of cancer include viruses, immune system issues, genetics, environment and age. However, a lack of particular co-stimulated molecules that aid in the way antigens react with lymphocytes can impair the natural killer cells ability and ultimately cause cancer. All cancers begin in cells, the body's basic unit of life. To understand cancer, it's helpful to know what happens when normal cells become cancer cells. The body is made up of many types of cells. These cells grow and are controlled to produce more cells as they are needed to keep the body healthy. When cells become old or damaged, they die and are replaced with new cells. Sometimes this process of controlled production of cells goes wrong. The genetic material (DNA) of a cell start producing mutations that affect normal cell growth and division by being damaged. When this happens, these cells do not die but form a mass of tissue called a tumor. Said mutations accumulate, being another reason that cancer is found more often in older people. White Blood cells are thought to use a dual receptor system when they determine whether or not to kill human cells. If a cell is under stress, turning into tumors, or infected molecules including MIC-A and MIC-B are produced to put on the surface of the cell. These work to detect and kill cancer cells. Some descriptions of cancer go back to ancient Egypt as far back as 1600 BC and the understanding of cancer was significantly advanced during the Renaissance period. However, Sir Rudolf Virchow, a German biologist and politician, is generally credited with discovering the first cancer cells. As Giovanni Morgagni had linked autopsy findings seen with the unaided eye with the clinical course of illness, so Virchow correlated the microscopic pathology. Cancer cells have unique features that make them "immortal" according to some researchers. The enzyme telomerase is used to extend the cancer cell's life span. While the telomeres of most cells shortens after each division eventually causing the cell to die, telomerase extends the cell's telomeres. This is a major reason that cancer cells can accumulate over time creating tumors. M: NEO tsoc, mrkr tumr, epon, para drug (L1i/1e/V03)

Programmed cell death
Programmed cell-death (or PCD) is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development. Apoptosis and autophagy are both forms of programmed cell death, however necrosis is a non-physiological process that occurs as a result of infection or injury. Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed Necrosis, also called Necroptosis has been recognized as an alternate form of programmed cell death. It is hypothesized that Necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that in a developmental context cells are induced to positively commit suicide whilst in a homeostatic context the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors. Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, Stress (physiology), Infection and cancer. A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy. The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12–Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane. Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator. Besides the above two types of PCD, other pathways have been discovered. Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD. Other forms of programmed cell death include anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity and Wallerian degeneration. Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa. An atrophic factor is a force that causes a cell to die. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors.][ Common types of atrophic factors are: The concept of "programmed cell-death" was used by Lockshin & Williams in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. Since then, PCD has become the more general of these two terms. The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves. PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK). Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, the most obvious being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies. In "APL regulates vascular tissue identity in Arabidopsis", Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell-types "the differentiation of which involves deposition of elaborate cell-wall thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role. Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms. It should be noted, however, that specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosis—for instance, nuclear DNA degradation—but they also have their own peculiarities, such as nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem. Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells. During pollination, plants enforce self-incompatibility (SI) as an important means to prevent self-fertilization. Research on the corn poppy (Papaver rhoeas) has revealed that proteins in the pistil on which the pollen lands, interact with pollen and trigger PCD in incompatible (i.e., self) pollen. The researchers, Steven G. Thomas and Veronica E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD. The social slime mold Dictyostelium discoideum has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation. The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of chromatin condensation, but no DNA fragmentation. The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue. D. discoideum is a slime mold, part of a branch that might have emerged from eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary tree, the fact that PCD has been observed in the humble, simple, six-chromosome D. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis. Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("living together inside") of larger eukaryotic cells. It was Lynn Margulis who from 1967 on championed this theory, which has since become widely accepted. The most convincing evidence for this theory is the fact that mitochondria possess their own DNA and are equipped with genes and replication apparatus. This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white blood cells and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the chemical warfare waged by prokaryotes to succeed, with the consequence known as infection by its resulting damage. One of these rare evolutionary events, about two billion years before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their symbiosis. Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide. This process has now been evolved to happen only when programmed.][ Given certain signals to cells (such as feedback from neighbors, stress or DNA damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives. The BCR-ABL oncogene has been found to be involved in the development of cancer in humans. c-Myc is involved in the regulation of apoptosis via its role in downregulating the Bcl-2 gene. Its role the disordered growth of tissue. A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes. M: OBS phys/devp/memb mthr/fetu/infc, epon proc, drug (2A/G2C)

Cancer stem cell
Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease. Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study. The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs would form a very small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause a relapse of the disease.
In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity, tumor are formed from cells with various proliferative and differentiate capacities. This functional heterogeneity among cancer cells lead to create at least two models, which have put forward to account for heterogeneity and differences in tumor-regenerative capacity, the cancer stem cells (CSC) and clonal evolution models The cancer stem cell model refers to a subset of tumor cells that have the ability to self-renew and are capable to generate the diverse tumor cells. These cells have been termed cancer stem cells to reflect their stem-like properties. One implication of the CSC model and the existence of CSCs is that the tumor population is hierarchically arranged with CSCs lying at the apex of the hierarchy (Fig. 3). The clonal evolution model postulates that mutant tumor cells with a growth advantage are selected and expanded. Cells in the dominant population have a similar potential for initiating tumor growth (Fig. 4). These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties (Fig. 5).
The existence of CSCs is a subject of debate within medical research, because many studies have not been successful in discovering the similarities and differences between normal tissue stem cells and cancer (stem) cells. Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis, and to sustain the growth of a tumor since differentiated cells (constrained by the Hayflick Limit) cannot divide indefinitely. However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties, there is no incentive to focus on a specific subpopulation. There is also debate on the cell of origin of CSCs - whether they originate from normal stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity). The first conclusive evidence for CSCs was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of leukaemic cells that expressed a specific surface marker CD34, but lacked the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that are histologically similar to the donor. In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the CSC paradigm argue that only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000. Further evidence comes from histology, the study of the tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells. The existence of leukaemic stem cells prompted further research into other types of cancer. CSCs have recently been identified in several solid tumors, including cancers of the:
Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models, e.g., based on the cell compartment method. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer. Considerable work needs to be done, however, before the clinical efficacy of such models is established. The origin of cancer stem cells is still an area of ongoing research. Several camps have formed within the scientific community regarding the issue, and it is possible that several answers are correct, depending on the tumor type and the phenotype the tumor presents. One important distinction that will often be raised is that the cell of origin for a tumor can not be demonstrated using the cancer stem cell as a model. This is because cancer stem cells are isolated from end-stage tumors. Therefore, describing a cancer stem cell as a cell of origin is often an inaccurate claim, even though a cancer stem cell is capable of initiating new tumor formation. With that caveat mentioned, various theories define the origin of cancer stem cells. In brief, CSC can be generated as: mutants in developing stem or progenitor cells, mutants in adult stem cells or adult progenitor cells, or mutant differentiated cells that acquire stem like attributes. These theories often do focus on a tumor's cell of origin and as such must be approached with skepticism. Some researchers favor the theory that the cancer stem cell is generated by a mutation in stem cell niche populations during development. The logical progression claims that these developing stem populations are mutated and then expand such that the mutation is shared by many of the descendants of the mutated stem cell. These daughter stem cells are then much closer to becoming tumors, and since there are many of them there is more chance of a mutation that can cause cancer. Another theory associates adult stem cells with the formation of tumors. This is most often associated with tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, it has long been expected that stem cells are responsible for tumor formation. This is a consequence of the frequent cell divisions of these stem cells (compared to most adult stem cells) in conjunction with the extremely long lifespan of adult stem cells. This combination creates the ideal set of circumstances for mutations to accumulate; accumulation of mutations is the primary factor that drives cancer initiation. In spite of the logical backing of the theory, only recently has an evidence appeared showing association represents an actual phenomenon. It is important to bear in mind that due to the heterogeneous nature of evidence it is possible that any individual cancer could come from an alternative origin. A third possibility often raised is the potential de-differentiation of mutated cells such that these cells acquire stem cell like characteristics. This is often used as a potential alternative to any specific cell of origin, as it suggests that any cell might become a cancer stem cell. Another related concept is the concept of tumor hierarchy. This concept claims that a tumor is a heterogeneous population of mutant cells, all of which share some mutations but vary in specific phenotype. In this model, the tumor is made up of several types of stem cells, one optimal to the specific environment and several less successful lines. These secondary lines can become more successful in some environments, allowing the tumor to adapt to its environment, including adaptation to tumor treatment. If this situation is accurate, it has severe repercussions on cancer stem cell specific treatment regime. Within a tumor hierarchy model, it would be extremely difficult to pinpoint the cancer stem cell's origin.
CSC, now reported in most human tumors, are commonly identified and enriched using strategies for identifying normal stem cells that are similar across the studies. The procedures include fluorescence-activated cell sorting (FACS) with antibodies directed at cell-surface markers and functional approaches including SP analysis (side population assay) or Aldefluor assay. The CSC-enriched population purified by these approaches is then implanted, at various cell doses, in immune-deficient mice to assess its tumor development capacity. This in vivo assay is called limiting dilution assay. The tumor cell subsets that can initiate tumor development at low cell numbers are further tested for self-renewal capacity in serial tumor capacity. CSC can also be identified by efflux of incorporated Hoechst dyes via multidrug resistance (MDR) and ATP-binding cassette (ABC) Transporters][. Another approach which has also been used for identification of cell subset enriched with in CSCs in vitro is sphere-forming assays. Many normal stem cells such as hematopoietics or stem cells from tissues are capable, under special culture conditioned, to form three-dimensional spheres, which can differentiate into multiple cell types. Similarly as normal stem cells, the CSCs isolated from brain or prostate tumors has also ability to form anchorage-independent spheres.
Data over recent years have indicated the existence of CSC in various solid tumors. For isolating CSC from solid and hematological tumors markers specific for normal stem cells of the same organ are commonly use. Nevertheless, a number of cell surface markers have proved useful for isolation of subsets enriched for CSC including CD133 (also known as PROM1), CD44, CD24, EpCAM (epithelial cell adhesion molecule, also known as epithelial specific antigen, ESA), THY1 and ATP-binding cassette B5 (ABCB5). CD133 (prominin 1) is a five-transmembrane domain glycoprotein expressed on CD34+ stem and progenitor cells, in endothelial precursors and fetal neural stem cells. It has been detected using its glycosylated epitope know as AC133. EpCAM (epithelial cell adhesion molecule, ESA, TROP1) is hemophilic CA2+-independent cell adhesion molecule expressed on the basolateral surface of most epithelial cells. CD90 (THY1) is a glycosylphosphatidylinositol glycoprotein anchored in the plasma membrane and involved in signal transduction. It may also mediate adhesion between thymocytes and thymic stroma. CD44 (PGP1) is an adhesion molecule that has pleiotropic roles in cell signaling, migration and homing. It has multiple isoforms, including CD44H, which exhibits high affinity for hyaluronate, and CD44V which has metastatic properties. CD24 (HSA) is a glycosylated glycosylphosphatidylinositol-anchored adhesion molecule, which has co-stimulatory role in B and T cells. ALDH is a ubiquitous aldehyde dehydrogenase family of enzymes, which catalyzes the oxidation of aromatic aldehydes to carboxyl acids. For instance, it has role in conversion of retinol to retinoic acid, which is essential for survival. The first solid malignancy from which CSCs were isolated and identified was breast cancer. Therefore these SCSs are the most intensely studied. Breast CSC have been enriched in CD44+CD24-/low, SP, ALDH+ subpopulations. However, recent evidence indicates that breast CSC are very phenotypically diverse population, and there is evidence that not only CSC marker expression in breast cancer cells is heterogeneous but also there exist many subsets of breast CSC. Last studies provide further support to this point. Both CD44+CD24- and CD44+CD24+ cell populations are tumor initiating cells, however CSC are most highly enriched using the marker profile CD44+CD49fhiCD133/2hi. CSCs have been reported in many brain tumors. The stem-like tumors cells have been identified using cell surface markers including CD133, SSEA-1 (stage-specific embryonic antigen-1), EGFR][ and CD44. However, there is uncertainties about the use of CD133 for identification of brain tumor stem-like cells, because tumorigenic cells are found in both CD133+ and CD133- cells in some gliomas, and some CD133+ brain tumor cells may not possess tumor-initiating capacity. Similarly, CSCs have also been reported in human colon cancer. For their identification, cell surface markers as CD133, CD44 and ABCB5, or functional analysis including clonal analysis or Aldefluor assay were used using CD133 as positive marker for colon CSCs has generated conflicting results. Nevertheless, recent studies indicated that the AC133 epitope, but not the CD133 protein, is specifically expressed in colon CSCs and its expression is lost upon differentiation. In addition, using CD44+ colon cancer cells and additional sub-fractionation of CD44+EpCAM+ cell population with CD166 enhance the success of tumor engraftments. Multiple CSCs have been reported in prostate, lung and many other organs cancer, including liver, pancreas, kidney or ovary. In prostate cancer, the tumor-initiating cells have been identified in CD44+ cell subset as CD44+α2β1+, TRA-1-60+CD151+CD166+ or ALDH+ cell populations. Putative markers for lung CSCs have been reported, including CD133+, ALDH+, CD44+ and oncofetal protein 5T4+.
Metastasis is the major cause of tumor lethality in patients. However, not every cell in the tumor has the ability to metastasize. This potential depends on factors that determine growth, angiogenesis, invasion and other basic processes of tumor cells. In the many epithelial tumors, the epithelial-mesenchymal transition (EMT) is considered as a crucial events in the metastatic process. EMT and the reverse transition from mesenchymal to an epithelial phenotype (MET) are involved in embryonic development, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype. The EMT appears to be controlled by canonical pathways such as WNT and transforming growth factor β pathway. The important feature of EMT is the loss of membrane E-cadherin in adherent junctions, where the β-catenin may play a significant role. Translocation of β-catenin from adherent junctions to the nucleus may lead to a loss of E-cadherine, and subsequently to EMT. There is an evidence that nuclear β-catenin can directly transcriptionally activate EMT-associated target genes, such as the E-cadherine gene repressor SLUG (also known as SNAI2). Recent data have supported the concept, that tumor cells undergoing an EMT could be precursors for metastatic cancer cells, or even metastatic CSCs. In the invasive edge of pancreatic carcinoma a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells has been defined. These cells exhibited significantly stronger migratory activity than their counterpart CD133+CXCR4- cells, but both cell subsets showed similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor led to the reduced metastatic potential without altering tumorigenic capacity. On the other hand, in the breast cancer CD44+CD24-/low cells are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant metastases in patients with breast cancer. Although, there are only few data on mechanisms mediating metastasis in breast cancer, it is possible that CD44+CD24-/low cells initially metastasize and in the new site they change their phenotype and undergo limited differentiation. These findings led to new dynamic two-phase expression pattern concept based on the existence of two forms of cancer stem cells - stationary cancer stem cells (SCS) and mobile cancer stem cells (MCS). SCS are embedded in tissue and persist in differentiated areas throughout all tumor progression. The term MCS describes cells that are located at the tumor-host interface. There is an evidence that these cells are derived from SCS through the acquisition of transient EMT (Fig. 7)
The existence of CSCs has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies. Normal somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps (such as MDR][) that pump out drugs and DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells)][. CSCs that developed from normal stem cells may also produced these proteins that could increase their resistance towards chemotherapeutic agents. The surviving CSCs then repopulate the tumor causing a relapse. By selectively targeting CSCs, it would be possible to treat patients with aggressive, non-resectable tumors, as well as preventing patients from metastasizing. The hypothesis suggests that upon CSC elimination, cancer could regress due to differentiation and/or cell death][. What fraction of tumor cells are CSCs and therefore need to be eliminated is not clear yet. A number of studies have investigated the possibility of identifying specific markers that may distinguish CSCs from the bulk of the tumor (as well as from normal stem cells). Proteomic and genomic signatures of tumors are also being investigated.][. In 2009, scientists identified one compound, Salinomycin, that selectively reduces the proportion of breast CSCs in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent. The cell surface receptor interleukin-3 receptor-alpha (CD123) was shown to be overexpressed on CD34+CD38- leukemic stem cells (LSCs) in acute myelogenous leukemia (AML) but not on normal CD34+CD38- bone marrow cells. Jin et al., then demonstrated that treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overal AML cell repopulation including the proportion of LSCs in secondary mouse recipients.
The design of new drugs for the treatment of CSCs will likely require an understanding of the cellular mechanisms that regulate cell proliferation. The first advances in this area were made with hematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease for which the origin of CSCs is best understood. It is now becoming increasingly clear that stem cells of many organs share the same cellular pathways as leukemia-derived HSCs. Additionally, a normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it or by inducing oncoprotein activity. The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells. The pathway appears to be active in CSCs of pediatric brain tumors. The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including hematopoietic, neural and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors. A particular branch of the Notch signaling pathway that involves the transcription factor Hes3 has been shown to regulate a number of cultured cells with cancer stem cell characteristics obtained from glioblastoma patients. These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt. Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide (induces oxidative stress, inhibits NF-κB signaling) for AML (leukemia), and possibly myeloma and prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Finally, the enzyme telomerase may qualify as a study subject in CSC physiology. GRN163L (Imetelstat) was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, then a potential cure may be achieved if there are no more CSCs to repopulate a cancer.

Hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the blood cells that give rise to all the other blood cells. They give rise to the myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells). The definition of hematopoietic stem cells has changed in the last two decades. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. HSCs constitute 1:10.000 of cells in myeloid tissue. HSCs are a heterogeneous population. Three classes of stem cells exist, distinguished by their ratio of lymphoid to myeloid progeny (L/M) in blood. Myeloid-biased (My-bi) HSC have low L/M ratio (>0, <3), whereas lymphoid-biased (Ly-bi) HSC show a large ratio (>10). The third category consists of the balanced (Bala) HSC for which 3 ≤ L/M ≤ 10. Only the myeloid-biased and -balanced HSCs have durable self-renewal properties. In addition, serial transplantation experiments have shown that each subtype preferentially re-creates its blood cell type distribution, suggesting an inherited epigenetic program for each subtype. HSCs are found in the bone marrow of adults, with large quantities in the pelvis, femur, and sternum. They are also found in umbilical cord blood and, in small numbers, in peripheral blood.][ Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe.][ The cells can be removed a liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).][ In order to harvest stem cells from the circulating peripheral, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induce cells to leave the bone marrow and circulate in the blood vessels.][. In mammalian embryology, the first definitive HSCs are detected in the AGM (Aorta-gonad-mesonephros), and then massively expanded in the Fetal Liver prior to colonising the bone marrow before birth. As stem cells, HSC are defined by their ability to replenish all blood cell types (Multipotency) and their ability to self-renew. It is known that a small number of HSCs can expand to generate a very large number of daughter HSCs. This phenomenon is used in bone marrow transplantation, when a small number of HSCs reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter HSCs must occur. Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal. There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically. It was originally believed that all HSC were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1lo SCA-1+ lin- c-kit+ HSC. The results of these clonal studies led to the notion of lineage bias. Using the ratio \rho = L/M of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) HSC repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3≤ρ≤10). Myeloid-biased (My-bi) HSC give rise to too few lymphocytes resulting in ratios 0<ρ<3, while lymphoid-biased (Ly-bi) HSC generate too few myeloid cells, which results in lymphoid-to-myeloid ratios of 10<ρ<oo. All three types are norm three types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin Interleukin 7 (IL-7). Subsequent to this, other groups confirmed and highlighted the original findings (refer to the excellent mini-review by Timm Schroeder). For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties. In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population Side population (SP) SCA-1+ lin- c-kit+ HSC. As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively. A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer, a fraction of HSCs creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g., thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas or clusters of cells look dull cobblestone-like under phase contrast microscopy, compared to the other HSCs, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and α4β1 integrins. HSCs have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis, HSCs may also settle in the liver or spleen and develop. This ability is the reason why HSCs may be harvested directly from the blood. With regard to morphology, hematopoietic stem cells resemble lymphocytes. They are non-adherent, and rounded, with a rounded nucleus and low cytoplasm-to-nucleus ratio. Since PHSC cannot be isolated as a pure population, it is not possible to identify them in a microscope. The above description is based on the morphological characteristics of a heterogeneous population, of which PHSC are a component. In reference to phenotype, hematopoeitic stem cells are identified by their small size, lack of lineage (lin) markers, low staining (side population) with vital dyes such as rhodamine 123 (rhodamineDULL, also called rholo) or Hoechst 33342, and presence of various antigenic markers on their surface. Many of these markers belong to the cluster of differentiation series, like: CD34, CD38, CD90, CD133, CD105, CD45, and also c-kit, - the receptor for stem cell factor. The hematopoietic stem cells are negative for the markers that are used for detection of lineage commitment, and are, thus, called Lin-; and, during their purification by FACS, a bunch of up to 14 different mature blood-lineage marker, e.g., CD13 & CD33 for myeloid, CD71 for erythroid, CD19 for B cells, CD61 for megakaryocytic, etc. for humans; and, B220 (murine CD45) for B cells, Mac-1 (CD11b/CD18) for monocytes, Gr-1 for Granulocytes, Ter119 for erythroid cells, Il7Ra, CD3, CD4, CD5, CD8 for T cells, etc. (for mice) antibodies are used as a mixture to deplete the lin+ cells or late multipotent progenitors (MPP)s. There are many differences between the human and mice hematopoietic cell markers for the commonly accepted type of hematopoietic stem cells.[1]. However, not all stem cells are covered by these combinations that, nonetheless, have become popular. In fact, even in humans, there are hematopoietic stem cells that are CD34-/CD38-. Also some later studies suggested that earliest stem cells may lack c-kit on the cell surface. For human HSCs use of CD133 was one step ahead as both CD34+ and CD34- HSCs were CD133+. Traditional purification method used to yield a reasonable purity level of mouse hematopoietic stem cells, in general, requires a large(~10-12) battery of markers, most of which were surrogate markers with little functional significance, and thus partial overlap with the stem cell populations and sometimes other closely related cells that are not stem cells. Also, some of these markers (e.g., Thy1) are not conserved across mouse species, and use of markers like CD34- for HSC purification requires mice to be at least 8 weeks old. Alternative methods that could give rise to similar or better harvest of stem cells is a hot area of research and are presently emerging. One such method uses a signature of SLAM family of cell surface molecules. SLAM (Signaling lymphocyte activation molecule) family is a group of >10 molecules whose genes are located mostly tandemly in a single locus on chromosome 1 (mouse), all belonging to a subset of immunoglobulin gene superfamily, and originally thought to be involved in T-cell stimulation. This family includes CD48, CD150, CD244, etc., CD150 being the founding member, and, thus, also called slamF1, i.e., SLAM family member 1. The signature SLAM code for the hemopoietic hierarchy are: For HSCs, CD150+CD48- was sufficient instead of CD150+CD48-CD244- because CD48 is a ligand for CD244, and both would be positive only in the activated lineage-restricted progenitors. It seems that this code was more efficient than the more tedious earlier set of the large number of markers, and are also conserved across the mouse strains; however, recent work has shown that this method excludes a large number of HSCs and includes an equally large number of non-stem cells. . CD150+CD48- gave stem cell purity comparable to Thy1loSCA-1+lin-c-kit+ in mice. Irving Weissman's group at Stanford University was the first to isolate mouse hematopoietic stem cells in 1988 and was also the first to work out the markers to distinguish the mouse long-term (LT-HSC) and short-term (ST-HSC) hematopoietic stem cells (self-renew-capable), and the Multipotent progenitors (MPP, low or no self-renew capability — the later the developmental stage of MPP, the lesser the self-renewal ability and the more of some of the markers like CD4 and CD135): Between 1948 and 1950, the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood-forming Organs issued reports on the nomenclature of blood cells. An overview of the terminology is shown below, from earliest to final stage of development: The root for erythrocyte colony-forming units (CFU-E) is "rubri", for granulocyte-monocyte colony-forming units (CFU-GM) is "granulo" or "myelo" and "mono", for lympocyte colony-forming units (CFU-L) is "lympho" and for megakaryocyte colony-forming units (CFU-Meg) is "megakaryo". According to this terminology, the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte, metarubricyte, and erythrocyte. However, the following nomenclature seems to be, at present, the most prevalent: Osteoclasts also arise from hemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-GM. There are various kinds of colony-forming units: The above CFUs are based on the lineage. Another CFU, the colony-forming unit–spleen (CFU–S) was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or Transit Amplifying Cells rather than stem cells. Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC. The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes. To prove this, several hundred experimental repopulation kinetics from clonal Thy-1lo SCA-1+ lin- c-kit+ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria. Hematopoiesis bone: Osteoblast → Osteocyte Fibroblast → Fibrocyte muscle: Myoblast → Myocyte  Myosatellite cell  Tendon cell  Cardiac muscle cell Angioblast → Endothelial cell  Mesangial cell (Intraglomerular, Extraglomerular)  Juxtaglomerular cell  Macula densa cell Stromal cell → Interstitial cell → Telocytes M: BON/CAR anat (c/f/k/f, u, t/p, l)/phys/devp/cell noco/cong/tumr, sysi/epon, injr proc, drug (M5) M: URI anat/phys/devp/cell noco/acba/cong/tumr, sysi/epon, urte proc/itvp, drug (G4B), blte, urte M: VAS anat (a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot noco/syva/cong/lyvd/tumr, sysi/epon, injr proc, drug (C2s+n/3/4/5/7/8/9) M: MYL cell/phys (coag, heme, immu, gran), csfs rbmg/mogr/tumr/hist, sysi/epon, btst drug (B1/2/3+5+6), btst, trns M: LMC cell/phys/auag/auab/comp, igrc imdf/ipig/hyps/tumr proc, drug (L3/4)

Carcinogenesis
Carcinogenesis or oncogenesis or tumorigenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes at the cellular, genetic and epigenetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass. Cell division is a physiological process that occurs in almost all tissues and under many circumstances. Under normal circumstances, the balance between proliferation and programmed cell death, usually in the form of apoptosis, is maintained by tightly regulating both processes to ensure the integrity of organs and tissues. Mutations and epimutations in DNA that lead to cancer (only certain mutations and epimutations can lead to cancer and the majority of potential mutations and epimutations will have no bearing) disrupt these orderly processes by disrupting the programming regulating the processes. Carcinogenesis is caused by mutation and epimutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. The uncontrolled and often rapid proliferation of cells can lead to benign tumors; some types of these may turn into malignant tumors (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they compress vital structures or are physiologically active, for instance, producing a hormone. Malignant tumors can invade other organs, spread to distant locations (metastasis) and become life-threatening. More than one mutation is necessary for carcinogenesis. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. On average, for example, 15 "driver mutations" and 60 "passenger" mutations are found in colon cancers. Mutations in those certain types of genes that play vital roles in cell division, apoptosis (cell death), and mutations and epimutations (see article Genome instability) in DNA repair genes will cause a cell to lose control of its cell proliferation. Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host. This process is also referred to as viral transformation. Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered. Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes. There are two broad categories of genes that are affected by these changes. Oncogenes may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell. There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are also many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change that is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal region, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants. Epimutations include methylations or demethylations of the CpG islands of the promoter regions of genes, which result in repression or de-repression, respectively of gene expression. Epimutations, can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer. In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as HMGA2. A further source of epimutation is due to increased or decreased expression of microRNAs (miRNAs). For example extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers> DNA damage is considered to be the primary cause of cancer. More than 10,000 new naturally occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring). Additional DNA damages can arise from exposure to exogenous agents. As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer. DNA damages can also be caused by endogenous (naturally occurring) agents. Katsurano et al. indicated that macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis, and bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer. Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red. A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer with some defects causing up to 100% lifetime chance of cancer (e.g. p53 mutations [74]). Such germ line mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers. The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component. In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Five reports present evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region. Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, Pms2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1. In further examples [tabulated in the article Epigenetics (see section "DNA repair epigenetics in cancer")], epigenetic defects in cancers were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM in cancers including those in breast, ovarian, colorectal, and the head and neck areas. In particular, two or more epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 were shown to occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al. When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, more DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. For example, one group of studies shows that arsenic inhibits the DNA repair genes PARP, XRCC1, Ligase 3, Ligase 4, DNA POLB, XRCC4, DNA PKCS, TOPO2B, OGG1, ERCC1, XPF, XPB, XPC XPE and P53. Another group of studies shows that cadmium inhibits the DNA repair genes MSH2, ERCC1, XRCC1, OGG1, MSH6, DNA-PK, XPD and XPC The somatic mutations and epigenetic alterations caused by DNA damages and deficiencies in DNA repair accumulate in field defects. Field defects are normal appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and improperly proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations. It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists; for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco, so the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA damaging agents that occur both at the highest concentrations and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene. Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, 59 mutations shared by some, but not all regions, and 29 "private" mutations only present in one region. The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise. Field defects have been identified in association with cancers and are important in progression to cancer. However, it was pointed out by Rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" Similarly, Vogelstein et al. also indicated that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. It would also be expected that many of the epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects. In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. This may cause a patch of abnormal tissue to arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated (in the diagram below the photo) by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon. If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm. In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect. References in the table are given here: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size. Cancers are known to exhibit genome instability or a mutator phenotype. The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA. Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations. However, the average number of DNA sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (where melanomas have a higher exome mutation frequency) the total number of DNA sequence mutations is about 80,000. These high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defect giving rise to a cancer (e.g. yellow area in the diagram in the preceding section) is a deficiency in DNA repair. The large field defects surrounding colon cancers (extending to about 10 cm on each side of a cancer) were shown by Facista et al. to frequently have epigenetic defects in 2 or 3 DNA repair proteins (ERCC1, XPF and/or PMS2) in the entire area of the field defect. When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of mutation and/or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations and/or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made. Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy (numerical and structural abnormalities in chromosomes) rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species (figure). This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis) and the accumulation of reactive oxygen species leading to oxidative stress (oxidative stress theory of cancer). All these theories of carcinogenesis may be complementary rather than contradictory. Another theory as to the origin of cancer was developed by astrobiologists and suggests that cancer is an atavism, an evolutionary throwback to an earlier form of multicellular life. The genes responsible for uncontrolled cell growth and cooperation between cancer cells are very similar to those that enabled the first multicellular life forms to group together and flourish. These genes still exist within the genome of more complex metazoans, such as humans, although more recently evolved genes keep them in check. When the newer controlling genes fail for whatever reason, the cell can revert to its more primitive programming and reproduce out of control. The theory is an alternative to the notion that cancers begin with rogue cells that undergo evolution within the body. Instead they possess a fixed number of primitive genes that are progressively activated, giving them finite variability. Often, the multiple genetic changes that result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation. The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible. Just like a population of animals undergoes evolution, an unchecked population of cells also can undergo evolution. This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are out-competed. This is exactly how pathogens such as MRSA can become antibiotic-resistant (or how HIV can become drug-resistant), and the same reason why crop blights and pests can become pesticide-resistant. This evolution is why cancer recurrences will have cells that have acquired cancer-drug resistance (or in some cases, resistance to radiation from radiotherapy). In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows: The completion of these multiple steps would be a very rare event without : These biological changes are classical in carcinomas; other malignant tumors may not need to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells. Cancer is a genetic disease: In order for cells to start dividing uncontrollably, genes that regulate cell growth must be damaged. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. This concept is sometimes termed "oncoevolution." Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably. But the uncontrolled cell division that characterizes cancer also requires that the dividing cell duplicates all its cellular components to create two daughter cells. The activation of anaerobic glycolysis (the Warburg effect), which is not necessarily induced by mutations in proto-oncogenes and tumor suppressor genes, provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis. There are several different cell types that are critical to tumour growth. In particular endothelial progenitor cells are a very important cell population in tumour blood vessel growth. The hypothesis that endothelial progenitor cells are important in tumour growth, angiogenesis and metastasis has been supported by a recent publication in Cancer Research (August 2010). This paper argues that endothelial progenitor cells can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators were able to track endothelial progenitor cells from the bone marrow to the blood to the tumour-stroma and vasculature. This finding of endothelial progenitor cells incorporated in tumour vasculature gives evidence for the importance of this cell type in blood vessel development in a tumour setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. The continued research into the importance of endothelial progenitor cells may present novel therapeutic targets. Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to affect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive. One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also, when ligated to a stimulating control element, it could induce cancers in cell line cultures. Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes is responsible for producing the products and biochemicals cells use and interact with. Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. It is important to note that a gene possessing a growth-promoting role may increase carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. This condition includes also the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes knowledge of the stage and type of cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies. Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage. Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis. The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway. However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer. Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene. Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations. Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process. In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first hypothesised by the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop. Usually, oncogenes are dominant alleles, as they contain gain-of-function mutations, whereas mutated tumor suppressors are recessive alleles, as they contain loss-of-function mutations. Each cell has two copies of a same gene, one from each parent, and, under most cases, gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation must happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional, called the dominant negative effect. This is observed in many p53 mutations. Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Rb mutations develop retinoblastoma. In similar fashion, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. A new idea announced in 2011 is an extreme version of multiple mutations, called chromothripsis by its proponents. This idea, affecting only 2–3% of cases of cancer, although up to 25% of bone cancers, involves the catastrophic shattering of a chromosome into tens or hundreds of pieces and then being patched back together incorrectly. This shattering probably takes place when the chromosomes are compacted during normal cell division, but the trigger for the shattering is unknown. Under this model, cancer arises as the result of a single, isolated event, rather than the slow accumulation of multiple mutations. Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer. Heliobacter pylori is known to cause MALT lymphoma. Other types of bacteria have been implicated in other cancers. Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection. The mode of virally induced tumors can be divided into two, acutely transforming or slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene. Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost. Depending on their location, cells can be damaged through radiation from sunshine, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage, a step on a path toward cancer. Cells often die if they are damaged, through failure of a vital process or the immune system; however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low. When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will suffer knock-outs. This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working. One concern is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth. Certain parasitic worms are known to be carcinogenic. These include: Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell. A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control. Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells. The cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis. While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment. Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment. Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution. Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertarial and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulative group dynamics.][ Radoslav S.Jovic-Cancer-released ancestor from our genes,www.newcancertheory.com M: NEO tsoc, mrkr tumr, epon, para drug (L1i/1e/V03)

Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells. Cell division usually occurs as part of a larger cell cycle. In eukaryotes, there are two distinct type of cell division: a vegetative division, whereby each daughter cell is genetically identical to the parent cell (mitosis), and a reductive cell division, whereby the number of chromosomes in the daughter cells is reduced by half, to produce haploid gametes (meiosis). Both of these cell division cycles are required in sexually reproducing organisms at some point in their life cycle, and both are believed to be present in the last eukaryotic common ancestor Prokaryotes also undergo a vegetative cell division known as binary fission, where their genetic material is segregated equally into two daughter cells. All cell divisions, regardless of organism, are preceded by a single round of DNA replication. For simple unicellular organisms such as the amoeba, one cell division is equivalent to reproduction – an entire new organism is created. On a larger scale, mitotic cell division can create progeny from multicellular organisms, such as plants that grow from cuttings. Cell division also enables sexually reproducing organisms to develop from the one-celled zygote, which itself was produced by cell division from gametes. And after growth, cell division allows for continual construction and repair of the organism. A human being's body experiences about 10,000 trillion cell divisions in a lifetime. Cell division has been modeled by finite subdivision rules. The primary concern of cell division is the maintenance of the original cell's genome. Before division can occur, the genomic information that is stored in chromosomes must be replicated, and the duplicated genome must be separated cleanly between cells. A great deal of cellular infrastructure is involved in keeping genomic information consistent between "generations". Cells are classified into two categories: simple, non-nucleated prokaryotic cells, and complex, nucleated eukaryotic cells. By dint of their structural differences, eukaryotic and prokaryotic cells do not divide in the same way. Also, the pattern of cell division that transforms eukaryotic stem cells into gametes (sperm cells in males or ova – egg cells – in females) is different from that of the somatic cell division in the cells of the body. Multicellular organisms replace worn-out cells through cell division. In some animals, however, cell division eventually halts. In humans this occurs on average, after 52 divisions, known as the Hayflick limit. The cell is then referred to as senescent. Cells stop dividing because the telomeres, protective bits of DNA on the end of a chromosome required for replication, shorten with each copy, eventually being consumed, as described in the article on telomere shortening. Cancer cells, on the other hand, are not thought to degrade in this way, if at all. An enzyme called telomerase, present in large quantities in cancerous cells, rebuilds the telomeres, allowing division to continue indefinitely.

Somatic evolution in cancer
Somatic evolution is the accumulation of mutations in the cells of a body during a lifetime, and the effects of those mutations on the fitness of those cells. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer. Cells in pre-malignant and malignant neoplasms (tumors) evolve by natural selection. This accounts for how cancer develops from normal tissue and why it has been difficult to cure. There are three necessary and sufficient conditions for natural selection, all of which are met in a neoplasm: Cells in neoplasms compete for resources, such as oxygen and glucose, as well as space. Thus, a cell that acquires a mutation that increases its fitness will generate more daughter cells than competitor cells that lack that mutation. In this way, a population of mutant cells, called a clone, can expand in the neoplasm. Clonal expansion is the signature of natural selection in cancer. Cancer therapies act as a form of artificial selection, killing sensitive cancer cells, but leaving behind resistant cells. Often the tumor will regrow from those resistant cells, the patient will relapse, and the therapy that had been previously used will no longer kill the cancer cells. This selection for resistance is similar to the repeatedly spraying crops with a pesticide and selecting for resistant pests until the pesticide is no longer effective. Modern descriptions of biological evolution will typically elaborate on major contributing factors to evolution such as the formation of local micro-environments, mutational robustness, molecular degeneracy, and cryptic genetic variation. Many of these contributing factors in evolution have been isolated and described for cancer. Cancer is a classic example of what evolutionary biologists call multilevel selection: at the level of the organism, cancer is usually fatal so there is selection for genes and the organization of tissues that suppress cancer. At the level of the cell, there is selection for increased cell proliferation and survival, such that a mutant cell that acquires one of the hallmarks of cancer (see below), will have a competitive advantage over cells that have not acquired the hallmark. Thus, at the level of the cell there is selection for cancer. The earliest ideas about neoplastic evolution come from Boveri who proposed that tumors originated in chromosomal abnormalities passed on to daughter cells. In the decades that followed, cancer was recognized as having a clonal origin associated with chromosomal aberrations. . Early mathematical modeling of cancer, by Armitage and Doll, set the stage for the future development of the somatic evolutionary theory of cancer. Armitage and Doll explained the cancer incidence data, as a function of age, as a process of the sequential accumulation of somatic mutations (or other rate limiting steps). Advances in cytogenetics facilitated discovery of chromosome abnormalities in neoplasms, including the Philadelphia chromosome in chronic myelogenous leukemia and translocations in acute myeloblastic leukemia. Sequences of karyotypes replacing one another in a tumor were observed as it progressed . Researchers hypothesized that cancer evolves in a sequence of chromosomal mutations and selection and that therapy may further select clones. In 1971, Knudson published the 2-hit hypothesis for mutation and cancer based on statistical analysis of inherited and sporadic cases of retinoblastoma. He postulated that retinoblastoma developed as a consequence of two mutations; one of which could be inherited or somatic followed by a second somatic mutation. Cytogenetic studies localized the region to the long arm of chromosome 13, and molecular genetic studies demonstrated that tumorigenesis was associated with chromosomal mechanisms, such as mitotic recombination or non-disjunction, that could lead to homozygosity of the mutation. The retinoblastoma gene was the first tumor suppressor gene to be cloned in 1986. Cairns hypothesized a different, but complementary, mechanism of tumor suppression in 1975 based on tissue architecture to protect against selection of variant somatic cells with increased fitness in proliferating epithelial populations, such as the intestine and other epithelial organs. He postulated that this could be accomplished by restricting the number of stem cells for example at the base of intestinal crypts and restraining the opportunities for competition between cells by shedding differentiated intestinal cells into the gut. The essential predictions of this model have been confirmed although mutations in some tumor suppressor genes, including CDKN2A (p16), predispose to clonal expansions that encompass large numbers of crypts in some conditions such as Barrett’s esophagus. He also postulated an immortal DNA strand that is discussed at Immortal DNA strand hypothesis. Nowell synthesized the evolutionary view of cancer in 1976 as a process of genetic instability and natural selection. Most of the alterations that occur are deleterious for the cell, and those clones will tend to go extinct, but occasional selectively advantageous mutations arise that lead to clonal expansions. This theory predicts a unique genetic composition in each neoplasm due to the random process of mutations, genetic polymorphisms in the human population, and differences in the selection pressures of the neoplasm’s microenvironment. Interventions are predicted to have varying results in different patients. What is more important, the theory predicts the emergence of resistant clones under the selective pressures of therapy. Since 1976, researchers have identified clonal expansions and genetic heterogeneity within many different types of neoplasms. It is known that there are multiple levels of genetic heterogeneity that are associated with cancer, including single nucleotide polymorphism (SNP), sequence mutations, Microsatellite shifts and instability, Loss of heterozygosity (LOH), Copy number variation (detected both by Comparative Genomic Hybridization (CGH), and array CGH, and karyotypic variations including chromosome structural aberrations and aneuploidy. Studies of this issue have focused mainly at the gene mutation level, as copy number variation, LOH and specific chromosomal translocations are explained in the context of gene mutation. It is thus necessary to integrate multiple levels of genetic variation in the context of complex system and multilevel selection. System instability is a major contributing factor for genetic heterogeneity. For the majority of cancers, genome instability is reflected at the chromosomal level and is referred to as chromosome instability or CIN. Genome instability is also referred to as an enabling characteristic for achieving endpoints of cancer evolution. Many of the somatic evolutionary studies have traditionally been focused on clonal expansion, as recurrent types of changes can be traced to illustrate the evolutionary path based on available methods. Recent studies from both direct DNA sequencing and karyotype analysis illustrate the importance of the high level of heterogeneity in somatic evolution. For the formation of solid tumors, there is an involvement of multiple cycles of clonal and non-clonal expansion. Even at the typical clonal expansion phase, there are significant levels of heterogeneity within the cell population, however, most are under-detected when mixed populations of cells are used for molecular analysis. In solid tumors, a majority of gene mutations are not recurrent types, and neither are the karyotypes. These analyses offer an explanation for the findings that there are no common mutations shared by most cancers. The state of a cell may be changed epigenetically, in addition to genetic alterations. The best-understood epigenetic alterations in tumors are the silencing or expression of genes by changes in the methylation of CG pairs of nucleotides in the promoter regions of the genes. These methylation patterns are copied to the new chromosomes when cells replicate their genomes and so methylation alterations are heritable and subject to natural selection. Methylation changes are thought to occur more frequently than mutations in the DNA, and so may account for many of the changes during neoplastic progression (the process by which normal tissue becomes cancerous), in particular in the early stages. Epigenetic changes in progression interact with genetic changes. For example, epigenetic silencing of genes responsible for the repair of mutations in the DNA (e.g. MLH1 and MSH2) results in an increase of genetic mutations. One common feature of neoplastic progression is the expansion of a clone with a genetic or epigenetic alteration. This may be a matter of chance, but is more likely due to the expanding clone having a competitive advantage (either a reproductive or survival advantage) over other cells in the tissue. Since clones often have many genetic and epigenetic alterations in their genomes, it is often not clear which of those alterations cause a reproductive or survival advantage and which other alterations are simply hitchhikers or passenger mutations (see Glossary below) on the clonal expansion. Clonal expansions are most often associated with the loss of the p53 (TP53) or p16 (CDKN2A/INK4a) tumor suppressor genes. In lung cancer, a clone with a p53 mutation was observed to have spread over the surface of one entire lung and into the other lung. In bladder cancer, clones with loss of p16 were observed to have spread over the entire surface of the bladder. Likewise, large expansions of clones with loss of p16 have been observed in the oral cavity and in Barrett's esophagus. Clonal expansions associated with inactivation of p53 have also appear in skin, Barrett's esophagus, brain, and kidney. Further clonal expansions have been observed in the stomach, bladder, colon, lung, hematopoietic (blood) cells, and prostate. These clonal expansions are important for at least two reasons. First, they generate a large target population of mutant cells and so increase the probability that the multiple mutations necessary to cause cancer will be acquired within that clone. Second, in at least one case, the size of the clone with loss of p53 has been associated with an increased risk of a pre-malignant tumor becoming cancerous. It is thought that the process of developing cancer involves successive waves of clonal expansions within the tumor. Phylogenetics may be applied to cells in tumors to reveal the evolutionary relationships between cells, just as it is used to reveal evolutionary relationships between organisms and species. Shibata, Tavare and colleagues have exploited this to estimate the time between the initiation of a tumor and its detection in the clinic. Louhelainen et al. have used parsimony to reconstruct the relationships between biopsy samples based on loss of heterozygosity. Phylogenetic trees should not be confused with oncogenetic trees, which represent the common sequences of genetic events during neoplastic progression and do not represent the relationships of common ancestry that are essential to a phylogeny. An adaptive landscape is a hypothetical topological landscape upon which evolution is envisioned to take place. It is similar to Wright's fitness landscape in which the location of each point represents the genotype of an organism and the altitude represents the fitness of that organism in the current environment. However, unlike Wright's rigid landscape, the adaptive landscape is pliable. It readily changes shape with changes in population densities and survival/reproductive strategies used within and among the various species. Wright’s shifting balance theory of evolution combines genetic drift (random sampling error in the transmission of genes) and natural selection to explain how multiple peaks on a fitness landscape could be occupied or how a population can achieve a higher peak on this landscape. This theory, based on the assumption of density-dependent selection as the principle forms of selection, results in a fitness landscape that is relatively rigid. A rigid landscape is one that does not change in response to even large changes in the position and composition of strategies along the landscape. In contrast to the fitness landscape, the adaptive landscape is constructed assuming that both density and frequency-dependent selection is involved (selection is frequency-dependant when the fitness of a species depends not only on that species strategy but also on the strategy of all other species). As such, the shape of the adaptive landscape can change drastically in response to even small changes in strategies and densities. The flexibility of adaptive landscapes provide several ways for natural selection to cross valleys and occupy multiple peaks without having to make large changes in their strategies. Within the context of differential or difference equation models for population dynamics, an adaptive landscape may actually be constructed using a Fitness Generating Function. If a given species is able to evolve, it will, over time, "climb" the adaptive landscape toward a fitness peak through gradual changes in its mean phenotype according to a strategy dynamic that involves the slope of the adaptive landscape. Because the adaptive landscape is not rigid and can change shape during the evolutionary process, it is possible that a species may be driven to maximum, minimum, or saddle point on the adaptive landscape. A population at a global maximum on the adaptive landscape corresponds an evolutionarily stable strategy (ESS) and will become dominant, driving all others toward extinction. Populations at a minimum or saddle point are not resistant to invasion, so that the introduction of a slightly different mutant strain may continue the evolutionary process toward unoccupied local maxima. The adaptive landscape provides a useful tool for studying somatic evolution as it can describe the process of how a mutant cell evolves from a small tumor to an invasive cancer. Understanding this process in terms of the adaptive landscape may lead to the control of cancer through external manipulation of the shape of the landscape. In their landmark paper, The Hallmarks of Cancer, Hanahan and Weinberg suggest that cancer can be described by a small number of underlying principles, despite the complexities of the disease. The authors describe how tumor progression proceeds via a process analogous to Darwinian evolution, where each genetic change confers a growth advantage to the cell. These genetic changes can be grouped into six "hallmarks", which drive a population of normal cells to become a cancer. The six hallmarks are: Genetic instability is defined as an "enabling characteristic" that facilitates the acquisition of other mutations due to defects in DNA repair. The hallmark "self-sufficiency in growth signals" describes the observation that tumor cells produce many of their own growth signals and thereby no longer rely on proliferation signals from the micro-environment. Normal cells are maintained in a nondividing state by antigrowth signals, which cancer cells learn to evade through genetic changes producing "insensitivity to antigrowth signals". A normal cell initiates programmed cell death (apoptosis) in response to signals such as DNA damage, oncogene overexpression, and survival factor insufficiency, but a cancer cell learns to "evade apoptosis", leading to the accumulation of aberrant cells. Most mammalian cells can replicate a limited number of times due to progressive shortening of telomeres; virtually all malignant cancer cells gain an ability to maintain their telomeres, conferring "limitless replicative potential". As cells cannot survive at distances of more than 100 μm from a blood supply, cancer cells must initiate the formation of new blood vessels to support their growth via the process of "sustained angiogenesis". During the development of most cancers, primary tumor cells acquire the ability to undergo "invasion and metastasis" whereby they migrate into the surrounding tissue and travel to distant sites in the body, forming secondary tumors. The pathways that cells take toward becoming malignant cancers are variable, and the order in which the hallmarks are acquired can vary from tumor to tumor. The early genetic events in tumorigenesis are difficult to measure clinically, but can be simulated according to known biology. Macroscopic tumors are now beginning to be described in terms of their underlying genetic changes, providing additional data to refine the framework described in The Hallmarks of Cancer. The theory about the monoclonal origin of cancer states that in general neoplasms arise from a single cell of origin. While it is possible that certain carcinogens may mutate more than one cell at once, the tumor mass usually represents progeny of a single cell, or very few cells. A series of mutations is required in the process of carcinogenesis for a cell to transition from being normal to pre-malignant and then to a cancer cell. The mutated genes usually belong to classes of caretaker, gatekeeper, landscaper or several other genes. Mutation ultimately leads to acquisition of the six hallmarks of cancer. The first malignant cell, that gives rise to the tumor, is often labeled a cancer stem cell. The cancer stem-cell hypothesis relies on the fact that a lot of tumors are heterogeneous – the cells in the tumor vary by phenotype and functions. Current research shows that in many cancers there is apparent hierarchy among cells. in general, there is a small population of cells in the tumor – about 0.2%–1% – that exhibits stem cell-like properties. These cells have the ability to give rise to a variety of cells in tumor tissue, self-renew indefinitely, and upon transfer can form new tumors. According to the hypothesis, cancer stem cells are the only cells capable of tumorigenesis – initiation of a new tumor. Cancer stem cell hypothesis might explain such phenomena as metastasis and remission. The monoclonal model of cancer and the cancer stem-cell model are not mutually exclusive. Cancer stem cell arises by clonal evolution as a result of selection for the cell with the highest fitness in the neoplasm. This way, the heterogeneous nature of neoplasm can be explained by two processes – clonal evolution, or the hierarchical differentiation of cells, regulated by cancer stem cells. All cancers arise as a result of somatic evolution, but only some of them fit the cancer stem cell hypothesis. The evolutionary processes do not cease when a population of cancer stem cells arises in a tumor. Cancer treatment drugs pose a strong selective force on all types of cells in tumors, including cancer stem cells, which would be forced to evolve resistance to the treatment. It is interesting to note that cancer stem cells do not always have to have the highest resistance among the cells in the tumor to survive chemotherapy and re-emerge afterwards. The surviving cells might be in a special microenvironment, which protects them from adverse effects of treatment. It is currently unclear as to whether cancer stem cells arise from adult stem cell transformation, a maturation arrest of progenitor cells, or as a result of dedifferentiation of mature cells. Therapeutic resistance has been observed in virtually every form of therapy, from the beginning of cancer therapy. In most cases, therapies appear to select for mutations in the genes or pathways targeted by the drug. Some of the first evidence for a genetic basis of acquired therapeutic resistance came from studies of methotrexate. Methotrexate inhibits the dihydrofolate reductase (DHFR) gene. However, methotrexate therapy appears to select for cells with extra copies (amplification) of DHFR, which are resistant to methotrexate. This was seen in both cell culture and samples from tumors in patients that had been treated with methotrexate. A common cytotoxic chemotherapy used in a variety of cancers, 5-fluorouracil (5-FU), targets the TYMS pathway and resistance can evolve through the evolution of extra copies of TYMS, thereby diluting the drug's effect. In the case of Gleevec (Imatinib), which targets the BCR-ABL fusion gene in chronic myeloid leukemia, resistance often develops through a mutation that changes the shape of the binding site of the drug. Sequential application of drugs can lead to the sequential evolution of resistance mutations to each drug in turn. Gleevec is not as selective as was originally thought. It turns out that it targets other tyrosine kinase genes and can be used to control gastrointestinal stromal tumors (GISTs) that are driven by mutations in c-KIT. However, patients with GIST sometimes relapse with additional mutations in c-KIT that make the cancer cells resistant to Gleevec. Gefitinib(Iressa) and Erlotinib (Tarceva) are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used for non-small cell lung cancer patients whose tumors have somatic mutations in EGFR. However, most patients' tumors eventually become resistant to these drugs. Two major mechanisms of acquired resistance have been discovered in patients who have developed clinical resistance to Gefitinib or Erlotinib: point mutations in the EGFR gene targeted by the drugs, and amplification of MET, another receptor tyrosine kinase, which can bypass EGFR to activate downstream signaling in the cell. In an initial study, 22% of tumors with acquired resistance to Gefitinib or Erlotinib had MET amplification. To address these issues, clinical trials are currently assessing irreversible EGFR inhibitors (which inihibit growth even in cell lines with mutations in EGFR), the combination of EGFR and MET kinase inhibitors, and Hsp90 inihibitors (EGFR and MET both require Hsp90 proteins to fold properly). In addition, taking repeated tumor biopsies from patients as they develop resistance to these drugs would help to understand the tumor dynamics. Selective estrogen receptor modulators (SERMs) are a commonly used adjuvant therapy in estrogen-receptor positive (ERα+) breast cancer and a preventive treatment for women at high risk of the disease. There are several possible mechanisms of SERM resistance, though the relative clinical importance of each is debated. These include: Most prostate cancers derive from cells that are stimulated to proliferate by androgens. Most prostate cancer therapies are therefore based on removing or blocking androgens. Mutations in the androgen receptor (AR) have been observed in anti-androgen resistant prostate cancer that makes the AR hypersensitive to the low levels of androgens that remain after therapy. Likewise, extra copies of the AR gene (amplification) have been observed in anti-androgen resistant prostate cancer. These additional copies of the gene are thought to make the cell hypersensitive to low levels of androgens and so allow them to proliferate under anti-androgen therapy. Resistance to radiotherapy is also commonly observed. However, to date, comparisons of malignant tissue before and after radiotherapy have not been done to identify genetic and epigenetic changes selected by exposure to radiation. In gliomas, a form of brain cancer, radiation therapy appears to select for stem cells, though it is unclear if the tumor returns to the pre-therapy proportion of cancer stem cells after therapy or if radiotherapy selects for an alteration that keeps the glioma cells in the stem cell state. Cancer drugs and therapies commonly used today are evolutionary inert and represent a strong selection force, which leads to drug resistance. A possible way to avoid that is to use a treatment agent that would co-evolve alongside with cancer cells. Anoxic bacteria could be used as competitors or predators in hypoxic environments within tumors. Scientists have been interested in the idea of using anoxic bacteria for over 150 years, but until recently there has been little progress in that field. According to Jain and Forbes, several requirements have to be met by the cells to qualify as efficient anticancer bacterium: 1.The bacterium cannot be toxic to the host 2.Its population should be restricted to the tumor mass 3.It should be able to disperse evenly throughout the neoplasm 4.At the end of the treatment bacterium should be easily eliminated from the host 5.It should not be causing severe immune response 6.It should be able to cause tumor cells death through competition for nutrients. In the process of the treatment cancer cells are most likely to evolve some form of resistance to the bacterial treatment. However, being a living organism, bacteria would coevolve with tumor cells, potentially eliminating the possibility of resistance. Since bacteria prefer an anoxic environment, they are not efficient at eliminating cells on the periphery of the tumor, where oxygen supply is efficient. A combination of bacterial treatment with chemical drugs will increase chances of destroying the tumor. Oncolytic viruses are engineered to infect cancerous cells. Limitations of that method include immune response to the virus and the possibility of the virus evolving into a pathogen. By manipulating the tumor environment we can create favorable conditions for the cells with least resistance to chemotherapy drugs to become more fit and outcompete the rest of the population. The chemotherapy, administered directly after, should wipe out the predominant tumor cells. Mapping between common terms from cancer biology and evolutionary biology M: NEO tsoc, mrkr tumr, epon, para drug (L1i/1e/V03)
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Cell cycle

The cell cycle, or cell-division cycle, is the series of events that take place in a cell leading to its division and duplication (replication). In cells without a nucleus (prokaryotic), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in three periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA—and the mitotic (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells" and the final phase, cytokinesis, where the new cell is completely divided. The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and hi some internal organs are renewed.

Carcinogenesis Carcinogens
The Hallmarks of Cancer

"The Hallmarks of Cancer" is a seminal peer-reviewed article published in the journal Cell in January 2000 by US cancer researchers Douglas Hanahan and Robert Weinberg.

The authors believe that the complexity of cancer can be reduced to a small number of underlying principles. The paper argues that all cancers share six common traits ("hallmarks") that govern the transformation of normal cells to cancer (malignant or tumor) cells.

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