The Role of Dopamine in Colon Cancer Neovascularization

描述(申请人提供)：该提案的长期目标是研究神经递质多巴胺(DA)在结肠癌新生血管中的作用。虽然在正常结肠组织中存在大量的内源性DA，但在恶性结肠肿瘤组织中存在大量的DA缺失。此外，我们最近证实DA抑制血管渗透因子/血管内皮生长因子(VPF/VEGF)诱导的血管生成，并且由于VPF/VEGF介导的血管生成促进结肠癌的生长和转移，因此DA也可能抑制肿瘤新生血管，从而抑制结肠癌的生长。本实验旨在研究DA在临床前结肠癌模型血管生成和血管生成中的作用。最后，将确定内源性结肠DA在结肠肿瘤血管生成和生长中的作用。目的I.探讨多巴胺对转移性结肠癌血管生成和生长的影响。实验设计：DA单独或联合常规抗癌药物对荷高转移性人结肠癌小鼠的抗血管生成和抗肿瘤效果。目的II.阐明多巴胺调节肿瘤新生血管的分子机制。实验设计：DA抑制血管生成和血管生成的信号通路(PKA和MAPK)将被阐明。目的III.探讨内源性DA在结肠癌血管生成和生长中的作用。实验设计：将在DA耗竭的小鼠和用特定的DA D2受体拮抗剂治疗的小鼠中测定肿瘤血管生成和生长的速度。最后，将确定结肠组织DA耗竭的机制(突触核蛋白介导)。这一建议所产生的知识不仅可能确定一种新的恶性结肠癌新生血管和生长调节因子，还可能为晚期结肠癌患者的治疗提供一种新的、有效的治疗方法。最重要的是，DA(一种小分子和相对便宜的药物)已经在临床上使用，并有既定的安全记录；因此，这项建议的任何积极发现都可以迅速转化为临床试验，用于治疗晚期结肠癌患者。

DESCRIPTION (provided by applicant): The long-term objective of the proposal is to investigate the role of neurotransmitter dopamine (DA) in colon tumor neovascularization. Although substantial amount of endogenous DA is present in normal colon tissues, in contrast there is loss of DA in malignant colon tumor tissues. Furthermore, as we have recently demonstrated that DA inhibits vascular permeability factor/ vascular endothelial growth factor (VPF/VEGF) induced angiogenesis and because VPF/VEGF mediated angiogenesis promotes growth and metastasis of colon cancer, it is therefore possible that DA may also inhibit tumor neovascularization and thereby growth of colon cancer. The experiments proposed here are designed to investigate the role of DA on angiogenesis and vasculogenesis in preclinical colon cancer model. Finally, the role of endogenous colon DA on colon tumor angiogenesis and growth will be ascertained. Aim I. To investigate the effect of DA on neovascularization and growth of metastatic colon cancer. Experimental Design: The anti-angiogenic and anti-tumor efficacy of DA either alone or in combination with conventional anticancer drugs in mice bearing highly metastatic orthotopic human colon cancer. Aim II. To elucidate the molecular mechanisms of DA mediated regulation of tumor neovascularization. Experimental Design: The signaling pathways (PKA and MAPK) through which DA inhibits angiogenesis and vasculogenesis will be elucidated. Aim III. To investigate the role of endogenous DA on the angiogenesis and growth of colon cancer. Experimental Design: the rate of tumor angiogenesis and growth will be determined in DA depleted mice and mice treated with specific DA D2 receptor antagonists. Finally, the mechanism (synuclein mediated) of depletion of colon tissue DA will be determined. The knowledge generated from this proposal may not only identify a novel regulator of malignant colon tumor neovascularization and growth, but can also suggest a newer and an effective therapy for the treatment of advanced colon cancer patients. Most importantly, DA (a small molecule and a relatively cheap drug) is already in clinical use with an established safety record; therefore any positive findings from this proposal can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced colon cancer patients.