Significance of angiogenesis in tumour progression and metastasis.

Angiogenesis is defined as a vascular neoformation usually of capillary origin. This phenomenon is important during development and under several physiological and or pathological conditions. In recent years, progress has been made to understand this phenomenon at the molecular level. This includes the identification of potent angiogenic factors, the appreciation of the role of proteases, the importance of the extracellular matrix, and the emerging characterisation of signal transduction pathways in endothelial cells. Two important participants in angiogenesis are molecules from the fibroblast growth factor (FGF) and the transforming growth factor-beta (TGF-beta) family. In our laboratory, we have extensively studied the roles and mechanisms of action of the major FGF prototype, FGF-2 and of the TGF-beta member, TGF-beta 1. Different isoforms of FGF-2 have been previously described, a high molecular weight (HMW) form associated with the nucleus and 18 kDa bFGF that is cytoplasmic. These two forms of FGF-2 also exhibit different functions when expressed endogenously. TGF-beta is formed from a latent complex by plasmin-dependent and plasmin-independent pathways. With the exception of macrophages, the plasmin-dependent pathway requires coculture conditions, urokinase, and the concentration of TGF-beta on the cell surface by the mannose-6-phosphate receptor and transglutaminase. Other important angiogenic modulators include vascular endothelial growth factor (VEGF) and angiostatin. The nature of the tumour angiogenesis factor is not yet known with certainty, but several identified and not yet identified angiogenic factors may act in concert. It is hoped that an angiostatic treatment for cancer will be derived from these molecular studies.