Question:

# How do cancer cells feed?

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

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)

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 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)

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.

cancer Genes

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" 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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