A SECRETED FGF-BINDING PROTEIN CAN SERVE AS THE ANGIOGENIC SWITCH IN HUMAN CANCER

The growth and metastatic spread of cancer is directly related to tumo r angiogenesis(1), and the driving factors need to be understood to ex ploit this process therapeutically(2,3). However, tumor cells and thei r normal stroma express a multitude of candidate angiogenic factors(2) , and very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contrib ute significantly to tumor angiogenesis(4-6) and metastasis(6-8). Here we investigated whether the expression in tumors of a secreted fibrob last growth factor (FGF)-binding protein (FGF-BP)(9) that mobilizes an d activates(10) locally stored FGFs (ref. 11) can serve as an angiogen ic switch molecule(3). Developmental expression of the retinoid-regula ted FGF-BP gene(12) is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult(13). The gene is, h owever, upregulated in carcinogen-induced skin tumors(13), in squamous cell carcinoma (SCC)(10) and in some colon cancer cell lines and tumo r samples. To assess the significance of FGF-BP expression in tumors, we depleted human SCC (ME-180) and colon carcinoma (LS174T) cell lines of their endogenous FGF-BP by targeting with specific ribozymes. We f ound that the reduction of FGF-BP reduced the release of biologically active basic FCF (bFGF) from cells in culture. Furthermore, the growth and angiogenesis of xenograft tumors in mice was decreased in paralle l with the reduction of FGF-BP. This suggests that human tumors can ut ilize FGF-BP as an angiogenic switch molecule.