Pharmacogenetics of Angiogenesis

Angiogenesis is a complex cascade of events involving extensive interplay between cells, soluble factors, and extracellular matrix components. Soluble factors including cytokines and growth factors have multifaceted stimulatory or inhibitory roles, thereby finely tuning the process. The angiogenic potential of tumors was initially demonstrated in animal models, and it is now recognized that angiogenesis not only precedes tumor growth but is also necessary for metastasis. Vascular endothelial growth factor (VEGF) plays a central role in prostate angiogenesis. Genetic variability of VEGF involves mainly the untranslated region of the gene and may be associated with increased VEGF transcription and protein expression. Indeed, the -1154G>A polymorphism increases VEGF transcription and has been associated with significantly increased risk of prostate cancer. Hypoxia inducible factor-1a (HIF-1a) is a transcription factor overexpressed in early stage prostate cancer; through its binding to hypoxic responsive elements, it activates the transcription of a wide variety of genes as a part of the cellular response to hypoxia, including VEGF, and potentially plays a key role in prostate cancer development and response to antiangiogenic drugs. Therefore, angiogenesis-related genes seem to have an important role in prostate cancer risk and aggressiveness, thus influencing the outcome of antiangiogenic treatments and survival of patients.