Gliomas are among the most malignant and most highly vascularized human tumors. We studied the therapeutic action of an angiostatic fragment of human thrombospondin 1 (named TSP1ang) on experimental glioma tumor growth. TSP1ang (enclosing amino acids 167-569) comprised the procollagen-homology domain and the three type I repeats of the original molecule. C6 glioma cells that stably express TSP1ang were generated, and their rate of in vitro growth did not appear to differ from that of C6 cells transfected with an empty plasmid. TSP1ang-expressing C6 cells were then injected either subcutaneously or intracerebrally into nude mice. The resulting tumors appeared to be less vascularized, but unexpectedly started to grow earlier and had a much more invasive phenotype than tumors derived from control C6 cells. They were also much more aggressive, since the mice bearing intracerebral TSP1ang-expressing tumor cells died before day 19 post-implantation, whereas all mice bearing control C6 tumors were alive at this time point. These results indicate that careful attention should be paid at designing smaller fragments from the multimodular angiostatic molecule TSP1 since, as observed in this study, it may unmask protumorigenic properties that counteract its antiangiogenic activity.