Overexpression of anti-apoptotic members of the BCL2 family. Overexpression of BCL2 is a common event leading to the protection of tumor cells from apoptosis and occurs through several mechanisms. One of the best understood examples is found follicular lymphoma (Chapter 12), a B-cell tumor carrying a characteristic (14;18) (q32;q21) translocation that fuses the BCL2 (located at 18q21) to the transcriptionally active immunoglobulin heavy chain gene (located at 14q32). The resulting overabundance of BCL2 protects lymphocytes from apoptosis and allows them to survive for abnormally long periods, producing a steady accumulation of B lymphocytes that results in lymphadenopathy. Because BCL2overexpressing follicular lymphomas arise in large part through reduced cell death rather than explosive cell proliferation, they tend to be indolent (slow-growing). In other tumors such as chronic lymphocytic leukemia (Chapter 12), it appears that BCL2 is upregulated because of loss of expression of specific micro-RNAs that normally dampen BCL2 expression. Many other mechanisms leading to overexpression of anti-apoptotic members of the BCL2 family have been described, particularly in the setting of resistance to chemotherapy. For example, amplification of the MCL1 gene is seen in a subset of lung and breast cancers.
Recognition of the mechanisms by which cancers evade cell death has stimulated several lines of targeted drug development. Restoration of p53 function in TP53-mutated tumors is a daunting problem (because of the inherent difficulty of “fixing” defective genes), but is possible in tumors in which p53 is inactive because of overexpression of its inhibitor, MDM2. Indeed, inhibitors of MDM2 that reactivate p53 and induce apoptosis in tumors with MDM2 gene amplification, such as certain types of sarcoma, are being tested in clinical trials. Even more promising results are being generated with drugs that mimic the activities of BH3-only proteins and inhibit the function of antiapoptotic members of the BCL2 family, particularly BCL2 itself. These drugs have potent activity against tumors characterized by BCL2 overexpression (such as chronic lymphocytic leukemia) and are likely to become a standard part of cancer treatment over the course of the next few years.
Evasionofcelldeathbycancersmainlyinvolvesacquiredabnormalitiesthatinterferewiththeintrinsic(mitochondrial)pathwayofapoptosis.
Themostcommonabnormalitiesinvolvelossofp53function,eitherbywayofTP53 mutationsoroverexpressionofthep53inhibitorMDM2.
Othercancersevadecelldeathbyoverexpressinganti-apoptoticmembersoftheBCL2family,suchasBCL2,BCL-XL,andMCL1,whichprotectcellsfromtheactionofBAXandBAK,thepro-apoptoticmembersoftheBCL2family.
InalargemajorityoffollicularB-celllymphomas,BCL2levelsarehighbecauseofa(14;18)translocationthatfusestheBCL2 genewithregulatoryelementsoftheimmunoglobulinheavychaingene.
InhibitorsofMDM2(whichactivatep53)andinhibitorsofBCL2familymembersinducethedeathofcancercellsbystimulatingtheintrinsicpathwayofapoptosisandarebeingdevelopedastherapeuticagents.
Tumor cells, unlike normal cells, are capable of limitless replication. As discussed previously in the context of cellular aging (Chapter 2), most normal human cells have a capacity of at most 70 doublings. Thereafter, the cells lose the ability to divide and enter replicative senescence. This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes.