Pergamon zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Europeanfoumnlo/CuNerVol. 31A, Nos. 718, pp. 11OL1104,1995 Copyright 0 1995 Elsevier Science Ltd Printed in Grea;Britain. AU rights reserved 0959-8049195 19.50+0.00 zyxwvutsr 0959-8049(95)00169-7 Significance of Angiogenesis in Tumour Progression and Metastasis A. Bikfalvi 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-p (TGF- p) 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-P member, TGF-Pl. 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-P 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-P 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. Key words: tumour angiogenesis, fibroblast growth factor-2, proteases EurJ Cancer, Vol. 31A, Nos 7/B, pp. 1101-l 104,1995 INTRODUCTION ANGIOGENESIS is defined as a process of vascular neoformation that occurs during development, menstruation and several pathological conditions such as neoplasia. Despite the fact that angiogenesis refers to the derivation of blood vessels of all types (micro and macrovessels), the term is usually restricted to the neoformation of capillary blood vessels. In recent years, a great effort has been made to dissect the molecular steps involved in neovascularisation. Several paracrine or autocrine factors that control the phenomenon have been identified, such as fibroblast growth factor (FGF), transforming growth factor-p (TGF-P) and vascular endothelial cell growth factor (VEGF) [l-3]. In addition, the role of extracellular matrix both as a reservoir of soluble angiogenic factors and as a source of essential signals is now understood [4]. Furthermore, the participation of urokinase type plasminogen activator (uPA), plasminogen activator inhibitor-l (PAI-I), collagenases or tissue metalloprotease inhibitor (TIMP) [S] in angiogenesis is now appreciated. uPA is not only important for matrix degradation Correspondence to A. Bikfalvi at Laboratoire CRRET, Universitk Paris XII, Ave du GknCral de Gaulle, CreteiWaris 94010 Cedex, France. The work presented here was completed af the Department of Cell Biology and the Kaplan Cancer Center and the Raymond and Beverly Sackler Foundation Laboratory, New York University Medical Center, 550 First Avenue, New York, New York 10016, U.S.A. EJC 31:1,8-E but may also provide signals for endothelial cell movement 16, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIH 71. The intracellular pathways leading to the formation of capillaries have not yet been elucidated. Several mechanisms for FGF-dependent or TGF-p-dependent signalling are emerging. In our laboratory, the roles of two participants in the control of neovascularisation, basic fibroblast growth factor (bFGF, FGF-2) and TGF-P, have been extensively investigated. In this review, we will summarise recent findings about the mechanisms of angiogenesis and the role of angiogenic and anti-angiogenic molecules in this process, emphasising the roles of FGF-2 and TGF-P. MOLECULAR MECHANISM OF ANGIOGENESIS Angiogenesis requires the coordinated activation of genes that are responsible for proliferation, migration and differentiation of endothelial cells to form capillary-like structures. The acti- vation of these genes is thought to occur through paracrine factors. To date, a limited number of these proteins have been identified. The genes activated by these factors encode autocrine/ intracrine secondary regulators, proteolytic enzymes, and mol- ecules that are direct downstream substrates of endothelial cytokine receptors. Basic fibroblast growth factor (FGF-2) is recognised as an important autocrine/intracrine regulator of endothelial cells [8]. 1101