Pocket Oncology (Pocket Notebook Series), 1st Ed.

DNA REPAIR & ANGIOGENESIS

Alexander Drilon

DNA Repair Mechanisms

• Mt that are not repaired before cell cycle replication can contribute to carcinogenesis, many DNA repair genes serve as TSGs & are often a/w inherited CA predisposition syndromes (Nat Rev Cancer 2012;12:801)

Angiogenesis

• Mediated by a number of growth factors & receptors including: (1) VEGF-VEGFR: Initiate angiogenesis, (2) ANG-TIE: Help maintain angiogenesis/vessel maturation → these are balanced by several inhibitors of angiogenesis (NEJM 2008;358:2039)

• VHL disease: Germline VHL Mt a/w hemangioblastomas, RCCs pheochromocytomas, PNETs; sporadic Mt also occur in RCCs

Figure 4-8 VHL/HIF pathway: Under normoxic conditions, O2 leads to hydroxyprolination of HIFα (HIF1A) that is tagged for degradation by the VHL protein; in the absence of O2 HIFα is not hydroxy-prolinated & free to heterodimerize with HIFβ in nucleus to ↑ transcription of target genes

Metastasis

• Involves a number of processes including met initiation (invasion, EMT, marrow mobilization, angiogenesis) → met progression (extravasation, vascular remodeling, immune evasion) → met virulence(organ-specific, “seed” vs. “soil” hypothesis) (NEJM 2008;358:2039)

• A variety of genes are involved in each of these steps, each of w/c confers an advantage to the CA cell at multiple points during its journey to a distant site

Suggested Readings/Websites: The Biology of Cancer, Weinberg 2013, Garland Science; Molecular Biology of Cancer, Pecorino 2012, Oxford; The Cancer Genome Atlas—http://cancergenome.nih.gov; My Cancer Genome—www.mycancergenome.org

Acknowledgment: Cancer biology chapters reviewed by Marc Ladanyi MD, Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center