The antitumor effects of pharmacologic inhibitors of angiogenesis are hampered in patients by the rapid development of
tumor resistance, notably through increased invasiveness and accelerated
metastasis. Here, we reevaluated the role of the endogenous antiangiogenic
thrombospondin 1 (TSP1) in prostate
carcinomas in which angiogenesis is an active process. In xenografted
tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered
tumor development. Our results show that TSP1 is a potent stimulator of prostate
tumor cell migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived
peptide. As suspected for pharmacologic inhibitors of angiogenesis, the TSP1 capacities to increase
hypoxia and to trigger cell migration are thus inherently linked. Importantly, although antiangiogenic TSP1 increases
hypoxia in vivo, our data show that, in turn,
hypoxia induced TSP1, thus generating a vicious circle in prostate
tumors. In radical
prostatectomy specimens, we found TSP1 expression significantly associated with invasive
tumors and with
tumors which eventually recurred. TSP1 may thus help select patients at risk of
prostate-specific antigen relapse. Together, the data suggest that intratumor disruption of the hypoxic cycle through TSP1 silencing will limit
tumor invasion.