Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization

The development of skin carcinomas presently is believed to be correlated w ith mutations in the p53 tumor suppressor and ras gene as well as with the loss of chromosome 9. We now demonstrate that, in addition, loss of chromos ome 15 may be a relevant genetic defect. Reintroduction of an extra copy of chromosome 15, but not chromosome 4, into the human skin carcinoma SCL-I c ells, lacking one copy of each chromosome, resulted in tumor suppression af ter s.c. injection in mice. Transfection with thrombospondin-1 (TSP-1), map ped to 15q15, induced the same tumor suppression without affecting cell pro liferation in vitro or in vivo. Halted tumors remained as small cysts encap sulated by surrounding stroma and blood vessels. These cysts were character ized by increased TSP-1 matrix deposition at the tumor/stroma border and a complete lack of tumor vascularization. Coinjection of TSP-1 antisense olig onucleotides drastically reduced TSP-1 expression and almost completely abo lished matrix deposition at the tumor/stroma border. As a consequence, the tumor phenotype reverted to a well vascularized, progressively expanding, s olid carcinoma indistinguishable from that induced by the untransfected SCL -I cells. Thus, these data strongly suggest TSP-1 as a potential tumor supp ressor on chromosome 15, The data further propose an unexpected mechanism o f TSP-1-mediated tumor suppression. instead of interfering with angiogenesi s in general, in this system TSP-1 acts as a matrix barrier at the tumor/st roma border, which, by halting tumor vascularization, prevents tumor cell i nvasion and, thus, tumor expansion.