SIGNIFICANCE OF ANGIOGENESIS IN TUMOR PROGRESSION AND METASTASIS

Angiogenesis is defined as a vascular neoformation usually of capillar y origin. This phenomenon is important during development and under se veral physiological and or pathological conditions. In recent years, p rogress has been made to understand this phenomenon at the molecular l evel. This includes the identification of potent angiogenic factors, t he appreciation of the role of proteases, the importance of the extrac ellular matrix, and the emerging characterisation of signal transducti on pathways in endothelial cells. Two important participants in angiog enesis are molecules from the fibroblast growth factor (FGF) and the t ransforming growth factor-beta (TGF-beta) family. In our laboratory, w e have extensively studied the roles and mechanisms of action of the m ajor FGF prototype, FGF-2 and of the TGF-beta member, TGF-beta 1. Diff erent isoforms of FGF-2 have been previously described, a high molecul ar weight (HMW) form associated with the nucleus and 18 kDa bFGF that is cytoplasmic. These two forms of FGF-2 also exhibit different functi ons when expressed endogenously. TGF-beta is formed from a latent comp lex by plasmin-dependent and plasmin-independent pathways. With the ex ception of macrophages, the plasmin-dependent pathway requires cocultu re conditions, urokinase, and the concentration of TGF-beta on the cel l surface by the mannose-6-phosphate receptor and transglutaminase. Ot her important angiogenic modulators include vascular endothelial growt h factor (VEGF) and angiostatin. The nature of the tumour angiogenesis factor is not yet known with certainty, but several identified and no t yet identified angiogenic factors may act in concert. It is hoped th at an angiostatic treatment for cancer will be derived from these mole cular studies.