Inhibition of angiogenesis and tumorigenesis, and induction of dormancy byp53 in a p53-null thyroid carcinoma cell line in vivo

Our recent in vitro findings for suppression of thrombospondin-1 (TSP1; an antiangiogenic factor) expression by wild-type (wt) p53 in a p53-null thyro id carcinoma cell line, FRO, prompted us to investigate the in vivo effect of exogenous wt-p53 and TSP1 expression on tumor growth and angiogenesis of FRO xenografts in nude mice. Overexpression of TSP1, which did not affect the in vitro cell growth, significantly inhibited the in vivo tumor growth and neovascularization but not tumorigenesis; all the mice inoculated with FRO cells expressing TSP1 developed tumors, which were smaller and less vas cularized than those derived from FRO cells. In contrast restoration of wt- p53 expression, which reduced the in vitro cell growth rate, inhibited tumo rigenesis and induced a state of "dormancy". Thus, similar to 40 % of mice inoculated with FRO cells expressing wt-p53 (FRO-p53) were tumor free and t he remaining mice developed hypovascular rumors which remained small (less than or equal to 5 mm in size) for up to 60 days. Of interest, the phenotyp e of FRO-p53 tumors reverted to a well vascularized, progressively expandin g tumor by exogenous expression of vascular endothelial growth factor (a pr oangiogenic factor). Our data demonstrated wt-p53 inhibition of tumorigenes is and induction of dormancy by suppression of neovascularization in FRO ce lls. The results suggest that p53 gene therapy for thyroid carcinoma harbor ing p53 mutation may be more efficacious than we had expected from previous in vitro data.