C-CAM 1 is a cell adhesion molecule of the immunoglobulin supergene family. We showed that C-CAM 1 plays critical roles in prostate cancer initiation and progression and that loss of C-CAM 1 is an early event in prostate carcinogenesis. More importantly, we showed that reintroduction of C-CAM 1 into prostate cancer cells can reverse their cancerous growth and that reduction of C-CAM 1 expression, by C-CAM I antisense transfection, in nontumorigenic prostate epithelial cells induces their tumorigenicity. These results indicate that C-CAM 1 is a tumor suppressor. Although C-CAM1 expression in DU145 prostate cancer cells effectively inhibits in vivo tumor growth in mice, there is no significant difference in in vitro cell proliferation between control and C-CAM1-expressing cells. Thus, C-CAM1 expression may inhibit tumor growth by interfering with tumor interactions with host environment. Because angiogenesis is essential for the growth and progression of solid tumors, we hypothesized that C-CAM I acts by inhibiting tumor angiogenesis. We have preliminary data demonstrating that expression of C-CAM 1 in prostate cancer cells induces the release of a factor (C-CAM 1-induced factor (CIF)) that has strong antiangiogenic effects both in vitro and in vivo. Our preliminary results suggest that this anti-angiogenic effect is mediated by induction of endothelial cell apoptosis. C-CAM1 is therefore a promising target for prostate cancer therapy. Preclinical studies of a recombinant human C-CAM1 adenovirus revealed that it can markedly suppress prostate tumorigenicity. To fully exploit C-CAM I's therapeutic potential, it is essential to determine how C-CAM I suppresses tumors. In addition, combining C-CAM 1 therapy with existing therapies should produce more effective treatment. Therefore, we propose the following Specific Aims:
AIM #1 : To purify, identify, and clone CIF.
AIM #2 : To study whether a synergistic antitumor activity can be achieved by combining C-CAM1 with another antiangiogenic agent, TNP-470. Achieving these aims will provide valuable information for applying CCAM1 for prostate cancer therapy and for developing C-CAM1 combination therapy.
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