Angiogenesis and the role of epigenetics in metastasis.
The major obstacle to devising effective ways to treat cancer is its heterogeneity and genetic instability. It was originally postulated that targeting the process of tumor angiogenesis could circumvent this problem, as it involves genetically stable epigenetically controlled host stroma. Thus, anti-angiogenic approaches should be applicable across various tumor types and organ sites, including metastases. However, early clinical experience with this therapy revealed unexpectedly distinct responses between different tumors and organ sites. Here we propose that the heterogeneity of pre-clinical and clinical results obtained with anti-angiogenic agents stems from the deep functional linkage that may exist between genetic and epigenetic tumor progression. Thus, epigenetic processes regulating tumor associated host blood vessels (such as tumor microenvironment) display unstable, heterogeneous and progressive characteristics to an extent comparable with (and causally linked to) the instability of the cancer cell genome. As well, many known epigenetic factors (such as hypoxia, inflammation, expression of growth factors, etc.) may have genetic causes and consequences (e.g., oncogene expression, loss of tumor suppressor genes). This reciprocal interrelationship and heterogeneity may translate into site and stage specific changes in angiogenesis regulation, and angiogenesis dependence, ultimately to changes in the metastatic ability/efficiency of cancer cells, even in the same patient. A better understanding of the linkage between genetic and epigenetic events in growth and metastasis of various cancers may result in more effective use of anti-angiogenic therapy in future.
Coomber
Brenda L
BL
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada. bcoomber@uoguelph.ca
Yu
Joanne L
JL
Fathers
Kelly E
KE
Plumb
Claire
C
Rak
Janusz W
JW
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000517:prevention & control; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000517:prevention & control
D020533:Angiogenesis Inhibitors; D006133:Growth Substances