Progressing from Gene Mutations to Cancer
(2008) Abeloff’s Clinical Oncology — ISBN: [9780443066948], published
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- Abstract
- A root cause of cancer is the accumulation of defects in genes that play critical roles in regulating cell proliferation, cellular differentiation, and cell death. The mutations in cancer cells are of two types: gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. • Epigenetic mechanisms can substantially alter expression of proto-oncogenes and tumor suppressor genes, leading to essentially the same consequences as if the structure and/or sequence of the genes were affected by mutation. • Clinical and pathologic studies indicate that most cancers arise from pre-existing benign lesions, and it is estimated that six to seven mutations are needed for development of a clinically recognizable cancer. On the basis of molecular analyses of cancers, multiple gene defects may often accumulate in a cancer cell during its development, and benign lesions generally have fewer defects than do their malignant counterparts. • A process termed clonal selection has a key role in determining the particular constellation of genetic and epigenetic defects that are present in a cancer cell. Clonal selection is essentially a punctuated evolutionary process that promotes outgrowth of precancerous and cancerous cells carrying those mutations and gene expression changes that confer the most potent proliferative and survival properties upon the cancer cells, in a given context. • Although a diverse array of mutations and gene expression changes have been implicated in cancer pathogenesis, the defects appear to affect a more limited number of conserved signaling pathways or networks. The proto-oncogenes and tumor suppressor genes that are most frequently mutated in cancer cells most likely represent particularly critical hubs in the cell's regulatory circuitry. • Although cancer represents a very heterogeneous collection of diseases, the development of all cancers, regardless of type, appears to be critically dependent on the acquisition of certain traits that allow the cancer cells to grow in an unchecked fashion in their tissue of origin and to grow as metastatic lesions in distant sites in the body. Signature traits that are likely to be inherent in the majority, if not all, of cancer cells include the following: (1) an increased tendency to manifest a stem cell or progenitor-like phenotype, (2) an enhanced response to growth-promoting signals, (3) a relative resistance to growth inhibitory cues, (4) an increased mutation rate to allow for the rapid generation of new variant daughter cells, (5) the ability to attract and support a new blood supply (angiogenesis), (6) the capacity to minimize an immune response and/or evade destruction by immune effector cells, (7) the capacity for essentially limitless cell division, (8) a failure to respect tissue boundaries, allowing for invasion into adjacent tissues and organs as well as blood vessels and lymphatics, and (9) the ability to grow in organ sites with microenvironments that are markedly different from the one where the cancer cells arose. • Certain gene defects in cancer cells may contribute to a few or perhaps even only one of the signature traits of cancer cells. However, many of the gene defects and expression changes might have been selected for in large part because they exert pleiotropic effects on the cancer cell phenotype. • Despite the fact that some gene defects may arise early in the development of certain cancer types, advanced cancer cells might still be critically dependent on the “early gene defects” for continued growth and survival. Such findings imply that agents that specifically target key signaling pathways and proteins could have utility in advanced cancers even if the signaling pathway defect arose very early in cancer development. • Future studies will further clarify the role of gene defects in cancer phenotype, allowing more definitive and more specific strategies for inhibiting cancer cells.
- Affiliations
autre University of Michigan
Citations
Fearon, E., & Bommer, G. (2008). Progressing from Gene Mutations to Cancer. In Martin D. Abeloff, James O. Armitage, John E. Niederhuber, Michael B. Kastan, W. Gillies McKenna (ed.), Abeloff’s Clinical Oncology. Churchill Livingston Elsevier. https://hdl.handle.net/2078.5/205254