Chapter 080. Cancer Cell Biology and Angiogenesis (Part 3)

Figure 80-1Induction of p53 by the DNA damage and oncogene checkpoints.In response to noxious stimuli, p53 and mdm2 are phosphorylated by the ataxia telangiectasia mutated (ATM) and related ATR serine/threonine kinases, as well as the immediated downstream checkpoint kinases, Chk1 and Chk2. This causes dissociation of p53 from mdm2, leading to increased p53 protein levels and transcription of genes leading to cell cycle arrest (p21Cip1/Waf1) or apoptosis (e.g., the proapoptotic Bcl-2 family members Noxa and Puma). Inducers of p53 include hypoxia, DNA damage (caused by ultraviolet radiation, gamma irradiation, or chemotherapy), ribonucleotide depletion, and telomere shortening. A second mechanism...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 3) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 3)Figure 80-1 Induction of p53 by the DNA damage and oncogene checkpoints. In response to noxious stimuli, p53 and mdm2 are phosphorylated by theataxia telangiectasia mutated (ATM) and related ATR serine/threonine kinases, aswell as the immediated downstream checkpoint kinases, Chk1 and Chk2. Thiscauses dissociation of p53 from mdm2, leading to increased p53 protein levels andtranscription of genes leading to cell cycle arrest (p21Cip1/Waf1) or apoptosis (e.g.,the proapoptotic Bcl-2 family members Noxa and Puma). Inducers of p53 includehypoxia, DNA damage (caused by ultraviolet radiation, gamma irradiation, orchemotherapy), ribonucleotide depletion, and telomere shortening. A secondmechanism of p53 induction is activated by oncogenes such as Myc, whichpromote aberrant G1/S transition. This pathway is regulated by a second product ofthe Ink4a locus, p19ARF, which is encoded by an alternative reading frame of thesame stretch of DNA that codes for p16Ink4a. Levels of ARF are upregulated byMyc and E2F, and ARF binds to mdm2 and rescues p53 from its inhibitory effect.This oncogene checkpoint leads to the death or senescence (an irreversible arrestin G1 of the cell cycle) of renegade cells that attempt to enter S phase withoutappropriate physiologic signals. Senescent cells have been identified in patientswhose premalignant lesions harbor activated oncogenes, for instance, dysplasticnevi that encode an activated form of BRAF (see below), demonstrating thatinduction of senescence is a protective mechanism that operates in humans toprevent the outgrowth of neoplastic cells. Acquired mutation in p53 is the most common genetic alteration found inhuman cancer (>50%); germline mutation in p53 is the causative genetic lesion ofthe Li-Fraumeni familial cancer syndrome. In many tumors, one p53 allele onchromosome 17p is deleted and the other is mutated. The mutations often abrogatethe DNA binding function of p53 that is required for its transcription factoractivity and tumor-suppressor functions, and also result in high intracellular levelsof p53 protein. Inactivation of the p53 pathway compromises cell cycle arrest,attenuates apoptosis induced by DNA damage or other stimuli, and predisposescells to chromosome instability. This genomic instability greatly increases theprobability that p53 null cells will acquire additional mutations and becomemalignant. In summary, it is likely that all human cancers have genetic alterationsthat inactivate the Rb and p53 tumor-suppressor pathways. Tumors expressing mutant p53 are more resistant to radiation therapy andchemotherapy than tumors with wild-type p53. If the transcriptional functions ofthe mutant p53 could be reestablished in tumor cells, massive apoptosis mightensue, whereas normal cells would be protected because they express very lowlevels of wild-type p53. Investigators have screened chemical libraries forcompounds that inhibit tumor cell growth in a mutant p53-dependent manner. Onecompound entered cells and induced mutant p53 to adopt an active conformationsuch that p53-dependent transcriptional activation was restored and apoptosis wasselectively induced. This compound also had anti-tumor activity in murinexenograft models. Other investigators have identified a low-molecular-weight,cell-permeable compound that inhibits the apoptotic functions of wild-type p53found in normal host cells. This compound protected mice from the toxic effectsof radiation therapy and chemotherapy, including bone marrow suppression,gastrointestinal dysfunction, and hair loss. Taken together, these approachesprovide proof of principle for the pharmacologic manipulation of p53 function(mutant or wild-type) that could greatly enhance therapeutic efficacy whiledecreasing toxicity. Knowledge of the molecular events governing cell cycle regulation has ledto the development of viruses that replicate selectively in tumor cells with definedgenetic lesions. Such oncolytic viruses include adenoviruses designed toreplicate in tumor cells that lack functional p53 or have defects in the pRBpathway. The former group includes an adenovirus mutant in which the viral p55protein (which binds and inhibits p53) was deleted; this virus selectively replicatesin tumor cells lacking p53 function. This virus has shown efficacy in phase II clinical trials of head and necktumors, especially when combined with 5-fluorouracil and cisplatin (50% partialor complete response). The complexities of virus-host interactions (i.e., immuneresponse against replicating virus) will require further refinements of this noveltechnology before the clinical utility of this approach can be ...