Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC

The solid growth of high-grade glioma appears to be critically dependent on tumor angiogenesis, It remains unknown, however, whether the diffuse infil tration of glioma cells into healthy adjacent tissue is also dependent on t he formation of new tumor vessels. Here, we analyze the relationship betwee n tumor angiogenesis and tumor cell infiltration in an experimental glioma model. C6 cells were implanted into the dorsal skinfold chamber of nude mic e, and tumor angiogenesis was monitored by intravital fluorescence videomic roscopy, Glioma infiltration was assessed by the extent of tumor cell invas ion into the adjacent chamber tissue and by expression of SPARC, a cellular marker of glioma invasiveness, To test the hypothesis that glioma angiogen esis and glioma infiltration are codependent, we assessed tumor infiltratio n in both the presence and the absence of the angiogenesis inhibitor SU5416 , SU5416 is a selective inhibitor of the VEGF/FIk-I signal-transduction pat hway, a critical pathway implicated in angiogenesis, Control tumors demonst rated both high angiogenic activity and tumor cell invasion accompanied by strong expression of SPARC in invading tumor cells at the tumor-host tissue border. SU5416-treated tumors demonstrated reduced vascular density and va scular surface in the tumor periphery accompanied by marked inhibition of g lioma invasion and decreased SPARC expression. A direct effect of SU5416 on glioma cell motility and invasiveness was excluded by in vitro migration a nd invasion assays, These results suggest a crucial role for glioma-induced angiogenesis as a prerequisite for diffuse tumor invasion and a possible t herapeutic role for anti-angiogenic compounds as inhibitors of both solid a nd diffuse infiltrative tumor growth. Int, J, Cancer 87:261-268, 2000, (C) 2000 Wiley-Liss, Inc.