Regulation of Angiogenesis by C CAM1

C-CAM 1是免疫球蛋白的细胞粘附分子， 超基因家族我们发现C-CAM 1在前列腺中起着关键作用， 癌症的发生和发展，C-CAM 1的丢失是癌症发生和发展的早期事件。 前列腺癌更重要的是，我们发现， C-CAM 1进入前列腺癌细胞可以逆转其癌生长， 通过C-CAM I反义转染降低C-CAM 1表达， 非致瘤性前列腺上皮细胞诱导其致瘤性。这些 结果表明C-CAM 1是肿瘤抑制因子。虽然C-CAM 1表达 在DU 145前列腺癌细胞中， 小鼠，在体外细胞增殖之间没有显著差异 对照和C-CAM 1表达细胞。因此，C-CAM 1的表达可能抑制肿瘤的发生。 通过干扰肿瘤与宿主环境的相互作用来促进生长。因为 血管生成对于实体瘤的生长和进展至关重要，我们 假设C-CAM I通过抑制肿瘤血管生成而起作用。我们有 初步数据表明C-CAM 1在前列腺癌中的表达 细胞诱导释放一种因子（C-CAM 1诱导因子（CIF））， 在体外和体内都有很强的抗血管生成作用。我们的初步 结果表明，这种抗血管生成作用是通过诱导 内皮细胞凋亡因此，C-CAM 1是前列腺治疗的有希望的靶点。 癌症治疗重组人C-CAM 1腺病毒的临床前研究 显示其可显著抑制前列腺致瘤性。充分 为了开发C-CAM I的治疗潜力，必须确定C-CAM如何 我抑制肿瘤。此外，将C-CAM 1治疗与现有的 治疗应该产生更有效的治疗。因此，我们建议 目的#1：纯化、鉴定和克隆CIF。目标2： 为了研究是否可以通过联合使用来实现协同抗肿瘤活性， C-CAM 1与另一种抗血管生成剂TNP-470。实现这些目标将 为应用CCAM 1治疗前列腺癌提供了有价值的信息， 用于开发C-CAM 1联合疗法。

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.