Many carcinoma cells often express higher levels of transforming growth factor beta (TGFI3) than their normal counterparts. This is believed to generate TGFI3-resistant cancer cells through selection because TGF_ is a potent growth inhibitor in normal epithelial cells. As a result, many carcinoma cells are refractory to TGFp's growth inhibitory activity. On the other hand, ectopic expression of TGFp in transgenic mice or carcinoma cells promotes tumor progression in various cancer models. Exogenous TGFI3 has also been shown to stimulate angiogenesis in vivo. Thus, the increased TGFI3 production associated with carcinogenesis may also act to promote tumor progression. However, there are limited numbers of study that investigate whether antagonizing TGF_'s activity can inhibit tumor progression. During the last funding period, we have demonstrated that expression of a soluble TGFJ3 type III receptor (sRIII) can sequester active TGFI3 isoforms and inhibit tumor growth and metastasis of three human carcinoma cell lines suggesting that the endogenous TGFI3 in tumor environment can promote tumor progression. More recently, we have found that in vivo administration of a recombinant sRIII can significantly inhibit the growth and angiogenesis in human breast, prostate and colon xenograft models in nude mice. We have also found that treatment of human endothelial cells with the recombinant sRIII significantly inhibited their growth and their ability to form capillary tubule-like structure on an extracellular matrix. Currently, little is known about the role of autocrine TGFI3 signaling in controlling the growth of endothelial cells and their participation in angiogenesis. Therefore, for the competing renewal of our application, we propose to test our hypotheses that the recombinant sRIII may be utilized to suppress the malignancy of carcinomas and that the tumor- suppressive activity of sRIII is largely due to its antagonization against endogenous TGFI3's angiogenic activity. To test our hypotheses, we will determine the efficacy of tumor suppression with systemic administration of the recombinant sRIII, the anti-angiogenic activity of sRIII and the role of TGFI3 signaling in supporting the growth and angiogenicity of human endothelial cells. Accomplishment of our proposed work should reveal the mechanism by which the endogenous TGF_ stimulates tumor angiogenesis and whether TGFL3 antagonists such as sRIII have potential to become novel anti-cancer drugs.
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