Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor

Growth of tumors and metastasis are processes known to require neovasculari zation. To ascertain the participation of the endogenous angiogenic inhibit or thrombospondin-1 (TSP1) in tumor progression, we generated mammary tumor -prone mice that either lack, or specifically overexpress, TSP1 in the mamm ary gland. Tumor burden and vasculature were significantly increased in TSP 1-deficient animals, and capillaries within the tumor appeared distended an d sinusoidal. In contrast, TSP1 overexpressors showed delayed tumor growth or lacked frank tumor development (20% of animals); tumor capillaries showe d reduced diameter and were less frequent. Interestingly, absence of TSP1 r esulted in increased association of vascular endothelial growth factor (VEG F) with its receptor VEGFR2 and higher levels of active matrix metal-loprot einase-9 (MMP9), a molecule previously shown to facilitate both angiogenesi s and tumor invasion. In vitro, enzymatic activation of proMMP9 was suppres sed by TSP1. Together these results argue for a protective role of endogeno us inhibitors of angiogenesis in tumor growth and implicate TSP1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling.