Regulation of Angiogenesis by C CAM1

C-CAM1是免疫球蛋白的一种细胞黏附分子 表观基因家族。我们发现C-CAM1在前列腺癌中起着关键作用 癌症发生、发展和C-CAM1缺失是一种早期事件 前列腺癌的发生。更重要的是，我们展示了重新引入 C-CAM-1导入前列腺癌细胞可逆转其癌细胞生长 C-CAM I反义转染降低C-CAM-1的表达 非致瘤性前列腺上皮细胞诱导其致瘤性。这些 结果表明，C-CAM1是一种肿瘤抑制因子。虽然C-CAM1的表达 在DU145前列腺癌细胞体内有效抑制肿瘤生长 小鼠在体外细胞增殖方面无明显差异 对照组和表达C-CAM1的细胞。因此，C-CAM1的表达可能对肿瘤有抑制作用 通过干扰肿瘤与宿主环境的相互作用而生长。因为 血管生成对实体肿瘤的生长和发展是必不可少的，我们 推测C-CAM I通过抑制肿瘤血管生成发挥作用。我们有 前列腺癌中C-CAM-1表达的初步研究 细胞诱导释放一种因子(C-CAM 1诱导因子(CIF))，该因子具有 体外和体内均有较强的抗血管生成作用。我们的预赛 结果表明，这种抗血管生成作用是通过诱导 血管内皮细胞凋亡。因此，C-CAM1是前列腺癌的一个有希望的靶点 癌症治疗。重组人C-CAM1重组腺病毒的临床前研究 结果表明，它能显著抑制前列腺癌的致瘤性。充分地 开发C-CAM I的治疗潜力，关键是确定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 具体目标：目标1：纯化、鉴定和克隆CIF。目标2： 研究联合应用能否达到协同抗肿瘤活性 C-CAM1和另一种抗血管生成剂TNP-470。实现这些目标将 为将CCAM1应用于前列腺癌治疗提供有价值的信息 用于开发C-CAM1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.