Chapter 080. Cancer Cell Biology and Angiogenesis (Part 14)

Oncogene Addiction and Synthetic Lethality The concepts of oncogene addiction and synthetic lethality have spurred new drug development targeting oncogene and tumor-suppressor pathways. As discussed earlier in this chapter and outlined in Fig. 80-3, cancer cells become physiologically dependent upon signaling pathways containing activated oncogenes; this can effect proliferation (i.e., mutated Ras, BRAF, overexpressed Myc, or activated tyrosine kinases), survival (overexpression of Bcl-2 or NFκB), cell metabolism (as occurs when HIF-1α and Akt increase dependence on glycolysis), and perhaps angiogenesis (production of VEGF, e.g., renal cell cancer). In such cases, targeted inhibition of the pathway can lead to specific...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 14) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 14) Oncogene Addiction and Synthetic Lethality The concepts of oncogene addiction and synthetic lethality have spurrednew drug development targeting oncogene and tumor-suppressor pathways. Asdiscussed earlier in this chapter and outlined in Fig. 80-3, cancer cells becomephysiologically dependent upon signaling pathways containing activatedoncogenes; this can effect proliferation (i.e., mutated Ras, BRAF, overexpressedMyc, or activated tyrosine kinases), survival (overexpression of Bcl-2 or NFκB),cell metabolism (as occurs when HIF-1α and Akt increase dependence onglycolysis), and perhaps angiogenesis (production of VEGF, e.g., renal cellcancer). In such cases, targeted inhibition of the pathway can lead to specifickilling of the cancer cells. However, targeting defects in tumor-suppressor geneshas been much more difficult, since the target of the mutation is often deleted.However, identifying genes that have a synthetic lethal relationship to tumor-suppressor pathways may allow targeting of proteins required uniquely by thetumor cells (Fig. 80-3, panel B). Several examples of this have been identified. Forinstance, the von Hippel–Landau tumor-suppressor-protein is inactivated in 60%of renal cell cancers, leading to overexpression of HIF-1α and the subsequentactivation of downstream genes that promote angiogenesis, proliferation, survival,and altered glucose metabolism. HIF-1α mRNA has a complex 5-terminus thatindirectly requires the activity of mTOR (via activation of p70S6K and inhibitionof 4E-BP) for efficient protein translation. Inhibitors of mTOR block HIF-1αtranslation and have significant clinical activity in renal cell cancer. In this case,mTOR is synthetic lethal to VHL loss (Fig. 80-3), and its inhibition results inselective killing of cancer cells. Conceptually, this provides a framework forgenetic screens to identify other synthetic lethal combinations involving knowntumor-suppressor genes, and development of novel therapeutic agents to targetdependent pathways. In summary, our expanding knowledge of the genetic and molecularabnormalities in cancer cells, and their phenotypic correlates, has led to thedevelopment and FDA approval of a number of targeted pharmaceutical agents forthe treatment of cancer (Table 80-2). This list will expand to include inhibitors ofpathways currently under investigation and those yet to be discovered, yieldingnovel therapeutics with greater efficacy with less toxicity. Tumor Angiogenesis The growth of primary and metastatic tumors to larger than a fewmillimeters requires the recruitment of neighboring blood vessels and vascularendothelial cells to support their metabolic requirements. The diffusion limit foroxygen in tissues is ~100 µm. A critical element in the growth of primary tumorsand formation of metastatic sites is the angiogenic switch: the ability of the tumorto promote the formation of new capillaries from preexisting host vessels. Theangiogenic switch is a phase in tumor development when the dynamic balance ofpro- and antiangiogenic factors is tipped in favor of vessel formation by the effectsof the tumor on its immediate environment. Stimuli for tumor angiogenesisinclude hypoxia, inflammation, and genetic lesions in oncogenes or tumorsuppressors that alter tumor cell gene expression. Angiogenesis consists of severalsteps, including the stimulation of endothelial cells (ECs) by growth factors, thedegradation of the ECM by proteases, proliferation of ECs and migration into thetumor, and the eventual formation of new capillary tubes. Tumor blood vessels are not normal; they have chaotic architecture andblood flow. Due to an imbalance of angiogenic regulators such as VEGF andangiopoietins (see below), tumor vessels are tortuous and dilated with an unevendiameter, excessive branching, and shunting. Tumor blood flow is variable, withareas of hypoxia and acidosis leading to the selection of variants that are resistantto hypoxia-induced apoptosis (often due to the loss of p53 expression). Tumorvessel walls have numerous openings, widened interendothelial junctions, anddiscontinuous or absent basement membrane; this contributes to the high vascularpermeability of these vessels and, together with lack of functional intratumorallymphatics, causes interstitial hypertension within the tumor (which also interfereswith the delivery of therapeutics to the tumor; Figs. 80-8, 80-9, and 80-10). Tumorblood vessels lack perivascular cells such as pericytes and smooth-muscle cellsthat normally regulate flow in response to tissue metabolic needs. Figure 80-8