(Application Abstract) Although TGFb is an endogenous growth inhibitor for epithelial cells, this growth inhibitory response is often lost in solid tumors. Cancer cells displaying altered expression of TGFb receptors are among those that no longer display growth inhibitory sensitivity. However, the TGFb-resistant cells are still able to produce large quantities of the polypeptide. Since the paracrine effects of TGFb are largely tumor-enhancing, once the tumor epithelial cells have become refractory to TGFb-mediated growth inhibition, it would seem advantageous to shut off tumor cell TGFb production. This approach should reduce the paracrine, tumor-promoting effects of TGFb and could provide a novel alternative to strategies designed to restore TGFb growth inhibitory sensitivity to the resistant tumor cells. Our preliminary studies have revealed many of the signaling components which mediate TGFb1 production. The results of the proposed studies will define more subtle mechanisms which contribute to production of TGFb1, and will elucidate the production cascades for the TGFb2 and TGFb3 isoforms. We hypothesize that specific proteins in the TGFb production cascades are over-expressed or over-activated in late-stage tumors that have lost autocrine negative TGFb regulation due to TGFb receptor defects. We will examine the relevant signaling components in human colon carcinoma cells (HCCCs) in vitro and in colon, breast, and prostate cancer samples from patients. The latter molecular profiling studies will be performed with pure populations of cells procured by laser capture microdissection. We will also stably express antisense or wild-type versions of the relevant signaling components in HCCC model systems to determine the effect on the tumorigenic potential of the cancer cells in vitro and in vivo. Thus, the major objectives of this proposal are to delineate the components of the TGFb production cascades which are altered in human cancer cells in vitro and in vivo, and to determine whether blockade of these specific components will reduce tumor cell TGFb production, its paracrine effects on stromal cells, and its tumorigenic potential in vivo. Accordingly, the studies proposed in this application will demonstrate the potential utility of TGFb-based therapeutics against epithelial cancers which have progressed to the point of TGFB growth inhibitory insensitivity.
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