Down-regulation of caveolin-1, a candidate tumor suppressor gene, in sarcomas

Caveolae are plasma membrane microdomains that have been implicated in the regulation of several intracellular signaling pathways. Previous studies su ggest that caveolin-1, the main structural protein of caveolae, could funct ion as a tumor suppressor. Caveolin-1 is highly expressed in terminally dif ferentiated mesenchymal cells including adipocytes, endothelial cells, and smooth muscle cells. To study whether caveolin-1 is a possible tumor suppre ssor in human mesenchymal tumors, we have analyzed the expression using imm unohistochemistry in normal mesenchymal tissues, 22 benign and 79 malignant mesenchymal tumors. Caveolin-1 was found to be expressed in fibromatoses, leiomyomas, hemangiomas, and lipomas at high levels comparable to normal me senchymal tissues. The expression of caveolin-1 was slightly reduced in fou r of six well-differentiated liposarcomas and strongly reduced or lost in t hree of three fibrosarcomas, 17 of 20 leiomyosarcomas, 16 of 16 myxoid/roun d cell/pleomorphic liposarcomas, five of eight angiosarcomas, 15 of 18 mali gnant fibrous histiocytomas, and eight of eight synovial sarcomas. The immu nohistochemical findings were confirmed by Western blot analysis in a numbe r of tumors. High levels of both the 24-kd [alpha]- and the 21-kd [beta]-is oform of caveolin-1 were detected in the nontumorigenic human fibroblast ce ll line IMR-90. In contrast, in HT-1080 human fibrosarcoma cells, caveolin- 1 is strongly down-regulated. We show that the [alpha]-isoform of caveolin- 1 is potently up-regulated in HT-1080 cells by inhibition of the mitogen-ac tivated protein kinase-signaling pathway with the specific inhibitor PD 980 59, whereas the specific inhibitor of DNA methylation 5-aza-2'-deoxycytidin e only marginally up-regulates caveolin-1. In addition, re-expression of ca veolin-1 in HT-1080 fibrosarcoma cells potently inhibited colony formation. From these we conclude that caveolin-1 is likely to act as a tumor suppres sor gene in human sarcomas.