Identification of the target molecules for antiangiogenic therapy

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Head investigator has established a murine brain capillary endothelial cells (IBE cells) in 1996 and started the examination of FGF-2-mediated signal transduction pathways leading to angiogenesis. The purpose of the study is to identify specific signaling molecules involved in angiogenesis to make it possible to establish a new drug specifically and potently inhibit angiogenesis in vivo, such as tumor growth. IBE cells exhibit a panel of angiogenic cellular responses, such as urokinase production, proliferation, migration and tube formation. However, tube formation is rather specific for endothelial cells when compared with malignant tumor cells. By using this culture model, we found several important molecules as follows ;a. Blocking tube formation without any effect on proliferation by 4N1K peptide was enough to inhibit in vivo angiogenesis (mouse cornea micropocket assay). This result suggests the possibility that targeting tube formation is a good antiangiogenic strategy.b. c-Fes tyrosine kinase was involved in FGF-2-mediated chemotaxis and overexpression of wild type c-Fes induced FGF-2-independent tube formation.c. c-Src kinase was involved in chemotaxis toward FGF-2 by activating mitogen-activated protein kinase within focal adhesions.d. c-Fyn was transiently activated in IBE cells when cultured only on collagen gels (tube forming condition without proliferation or migration) and three stable cell lines expressing kinaseinactive c-Fyn exhibited attenuation of FGF-2-nediated tube formation (submitted). In the same study, it was found that c-Fes was activated by the adhesion of collagen gels. More recently, another growth factor was found to induce migration and tube formation. For migration, c-Fes was used and c-Fyn played a pivotal role in tube formation (submitted). Taken together, downstream molecules of c-Fes and c-Fyn would be potential targets of antiangiogenic therapy.