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

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 ta

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 killing of the cancer cells However, targeting defects in tumor-suppressor genes

has 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 the

tumor cells (Fig 80-3, panel B) Several examples of this have been identified For

instance, the von Hippel–Landau tumor-suppressor-protein is inactivated in 60%

of renal cell cancers, leading to overexpression of HIF-1α and the subsequent activation of downstream genes that promote angiogenesis, proliferation, survival, and altered glucose metabolism HIF-1α mRNA has a complex 5'-terminus that indirectly requires the activity of mTOR (via activation of p70S6K and inhibition

of 4E-BP) for efficient protein translation Inhibitors of mTOR block HIF-1α translation 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 in selective killing of cancer cells Conceptually, this provides a framework for genetic screens to identify other synthetic lethal combinations involving known tumor-suppressor genes, and development of novel therapeutic agents to target dependent pathways

In summary, our expanding knowledge of the genetic and molecular abnormalities in cancer cells, and their phenotypic correlates, has led to the development and FDA approval of a number of targeted pharmaceutical agents for the treatment of cancer (Table 80-2) This list will expand to include inhibitors of

pathways currently under investigation and those yet to be discovered, yielding novel therapeutics with greater efficacy with less toxicity

Tumor Angiogenesis

The growth of primary and metastatic tumors to larger than a few millimeters requires the recruitment of neighboring blood vessels and vascular endothelial cells to support their metabolic requirements The diffusion limit for oxygen in tissues is ~100 µm A critical element in the growth of primary tumors

and formation of metastatic sites is the angiogenic switch: the ability of the tumor

to promote the formation of new capillaries from preexisting host vessels The angiogenic switch is a phase in tumor development when the dynamic balance of pro- and antiangiogenic factors is tipped in favor of vessel formation by the effects

of the tumor on its immediate environment Stimuli for tumor angiogenesis include hypoxia, inflammation, and genetic lesions in oncogenes or tumor suppressors that alter tumor cell gene expression Angiogenesis consists of several steps, including the stimulation of endothelial cells (ECs) by growth factors, the degradation of the ECM by proteases, proliferation of ECs and migration into the tumor, and the eventual formation of new capillary tubes

Tumor blood vessels are not normal; they have chaotic architecture and blood flow Due to an imbalance of angiogenic regulators such as VEGF and angiopoietins (see below), tumor vessels are tortuous and dilated with an uneven

diameter, excessive branching, and shunting Tumor blood flow is variable, with areas of hypoxia and acidosis leading to the selection of variants that are resistant

to hypoxia-induced apoptosis (often due to the loss of p53 expression) Tumor vessel walls have numerous openings, widened interendothelial junctions, and discontinuous or absent basement membrane; this contributes to the high vascular permeability of these vessels and, together with lack of functional intratumoral lymphatics, causes interstitial hypertension within the tumor (which also interferes with the delivery of therapeutics to the tumor; Figs 80-8, 80-9, and 80-10) Tumor blood vessels lack perivascular cells such as pericytes and smooth-muscle cells that normally regulate flow in response to tissue metabolic needs

Figure 80-8