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CLONAL EVOLUTION-In 1976, Peter Nowell proposed a model of cancer as an evolutionary process in which a population of cells descended from a single cell of origin, or clone, acquires successive somatic mutations that allow sequential selection of fitter subclonesan evolution that underlies tumor progression, metastasis and resistance to therapy.
The gray circle represents a normal cell, and the central dot depicts the initiating somatic mutation that drives the founder clone in the tumor. The different colored circles represent subclones that have accumulated successive mutations. Note that in the primary tumor, several subclones coexist, and although some expand, others remain dormant or become extinct. Metastases can originate from either a major clone in the primary tumor (metastasis 1), or from minor clones (metastasis 2). Metastases can also undergo clonal evolution (as shown in metastasis 1). Each cell, when it divides, generates two identical new ones. So, when a cell acquires a mutation, it passes that mutation on to its progeny during cell growth and division. Because cells with cancerlinked mutations tend to proliferate more than normal cells, cellular candidates for additional mutations grow in number. Mutations continue to accumulate and are copied to descendant cells. If one cell finally acquires enough mutations to become cancerous, subsequent cancer cells will be derived from that one single transformed cell. So all tumors are clonal, which means that they originate from a single parent cell, whether that first mutant cell was of germline or somatic origin.
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A tumour (a neoplasm) is a solid or fluid-filled cystic lesion that may or may not be formed by an abnormal growth of neoplastic cells that appears enlarged in size. a tumor can be benign, pre-malignant, or malignant, or can represent a lesion without any cancerous potential whatsoever.
2) Insensitivity to antigrowth signalsWithin a normal tissue, multiple anti-proliferative signals (soluble growth inhibitors and immobilized inhibitors) operate to maintain cellular quiescence and tissue homeostasis. Antigrowth signals can block proliferation. Incipient cancer cells must evade these anti-proliferative signals if they are to prosper. All antiproliferative signals are funnelled through the retinoblastoma protein (pRb), basically pRb blocks proliferation by sequestering and altering the function of E2F transcription factors that control the expression of genes progressing from G1 into S phase. Disruption of the pRb pathway liberates E2F and allows cell proliferation. The pRb signalling circuit is governed by TGF- and other extrinsic factor can be disrupted in a variety of ways in different types of human tumors. Some lose TGF- responsiveness through downregulation of their TGF- receptors, while others display mutant, dysfunctional receptors. Cancer genetics-Aayudh Das Page 2
3) Evading ApoptosisThe ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation but also by the rate of cell attrition i.e. PCD-apoptosis. Acquired resistance toward apoptosis is a hallmark of most and perhaps all types of cancer. The apoptotic machinery can be broadly divided into two classes of components sensors and effectors. This sensory signal regulates the second class of components, which function as effectors of apoptotic death. The sentinels include cell surface receptors that bind survival or death factors. Examples of these ligand/receptor pairs include survival signals conveyed by IGF1/IGF-2 through their receptor, IGF-1R. Consequent apoptosis could be abrogated by exogenous survival factors (e.g., IGF-1), by forced overexpression of Bcl-2 or the related Bcl-XL protein, or by disruption of the FAS death signaling circuit.
5) Sustained Angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. Counterbalancing positive and negative signals encourage or block angiogenesis. Angiogenesis-initiating signals are like vascular endothelial growth factor (VEGF) that binds to transmembrane tyrosine kinase receptors. A prototypical angiogenesis inhibitor is thrombospondin-1, which binds to CD36, a transmembrane receptor on endothelial cells coupled to intracellular Src like tyrosine kinases. Tumors appear to activate the angiogenic switch by changing the balance of angiogenesis inducers and countervailing inhibitors. Many tumors evidence increased expression of VEGF compared to their normal tissue counterparts. In others, expression of endogenous inhibitors (thrombospondin-1) is downregulated.
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The most widely observed alteration in cell-to-environment interactions in cancer involves E-cadherin, a homotypic cell-to-cell interaction molecule ubiquitously expressed on epithelial cells. E-cadherin function is apparently lost in a majority of epithelial cancers, by mechanisms that include mutational inactivation of the E-cadherin or proteolysis of the extracellular cadherin domain.
cause either the loss of DNA, or the misexpression of genes. Situations of genome instability (as well as aneuploidy) are common in cancer cells, and they are considered a "hallmark" for these cells. 2) Tumor-Promoting Inflammation It is now clear that virtually every neoplastic lesion contains immune cells present at densities ranging from subtle infiltrations detectable only with cell type specific antibodies to gross inflammations that are apparent even by standard histochemical staining techniques. Inflammation can contribute to multiple hallmark capabilities by supplying bioactive molecules to the tumor microenvironment, including growth factors that sustain proliferative signalling, survival factors that limit cell death, pro-angiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis and other hallmark-facilitating programs. 3) Reprogramming Energy Metabolism The chronic and often uncontrolled cell proliferation deregulated control of energy metabolism in order to fuel cell growth and division. Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter to carbon dioxide in the mitochondria and under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria. In case of cancer cell even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed aerobic glycolysis. Glycolytic fueling has been shown to be associated with activated oncogenes (e.g., RAS, MYC) and mutant tumor suppressors (e.g., TP53) whose alterations in tumor cells have been selected primarily for their benefits in conferring the hallmark capabilities of cell proliferation. This reliance (dependence) on glycolysis can be further accentuated (highlight) under the hypoxic conditions that operate within many tumors: the hypoxia response system acts pleiotropically to upregulate glucose transporters and multiple enzymes of the glycolytic pathway. The hypoxic cancer cells depend on glucose for fuel and secrete lactate as waste. Oxygenation ranging from normoxia to hypoxia, is not necessarily static in tumors a result of the instability and chaotic organization of the tumor-associated neovasculature.
The immune system successfully recognizes and eliminates cancer cells, a process often described as the elimination phase Tumor cells not eliminated by the immune system proceed to the equilibrium phase, in which the immune system controls cancer cell growth but does not completely eliminate the transformed cells Tumor cells not susceptible to immune destruction progress into the escape phase. In this phase, the escaped tumor clonesnot effectively detected and destroyed by the immune systemcontinue to divide and grow Page 5
Clinical examples also support this finding, demonstrating that colorectal and ovarian cancer patients with an increased immune response have a better prognosis than do those patients with a reduced immune response
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