Pilot--Angiopoietins 1 & 2 in colon cancer angiogenesis

血管生成是由导致内皮细胞（EC） 增殖、侵袭、存活和分化。促血管生成活性 分子的量必须超过抗血管生成分子的量 新生血管形成除了诱导血管生成，肿瘤必须 在不利的环境条件下（缺氧或低 pH）。为了使EC在这些条件下存活，肿瘤必须分泌EC“存活 因素”。血管内皮生长因子（VEGF），一种重要的血管生成因子， 结肠癌进展和转移的因素，也已被证明是 EC生存因子。最近，血管生成素（Ang）配体家族已被发现。 在肿瘤血管生成中起重要作用。Ang- 1和Ang-2均结合 特异性EC受体Tie-2;然而，它们的生物学效应是 敌对Ang-I与Tie-2受体结合，引发血管生成素的活性。 这种跨膜受体的酪氨酸激酶活性。激活 Tie-2受体可稳定EC，抑制EC凋亡。 或者，Ang-2与Tie-2受体结合，但拮抗这种作用。 血管紧张素-1，导致EC不稳定和凋亡。协调 Ang-1、Ang-2和VEGF的诱导已经被证明是重要的。 诱导肿瘤血管生成。 本提案的总体目标是确定职能， 血管生成素在结肠癌血管生成中的调节。具体地说， 我们将确定： 1)血管紧张素-1和血管紧张素-2在结肠癌组织中相对表达 和正常粘膜。 2)Ang-1或Ang-2的过表达对肿瘤生长的影响， 血管生成和转移。 3)Ang-1和Ang-2过表达对肿瘤通透性的影响。 4)来自结肠癌细胞、周细胞和 非恶性细胞对内皮细胞Ang-1和Ang-2表达的影响。 此次试点的意义在于：（1）更加彻底地 了解血管生成素在“稳定”和 “破坏”肿瘤新血管系统的稳定可能会导致新的治疗方法 策略和/或（2）可以识别用于成像改变的 当暴露于抗血管生成剂时，

Angiogenesis is driven by specific factors that lead to endothelial ce1l (EC) proliferation, invasion, survival, and differentiation. The activity of pro-angiogenic molecules must exceed that of anti-angiogenic molecules to induce neovascularization. In addition to the induction of angiogenesis, tumors must support the vasculature under adverse environmental conditions (hypoxia or low pH). For ECs to survive in these conditions, tumors must secrete EC "survival factors". Vascular endothelial growth factor (VEGF), an important angiogenic factor in colon cancer progression and metastases, has also been shown to be an EC survival factor. Recently, the angiopoietin (Ang) family of ligands has been found to be important in tumor angiogenesis. Ang- 1 and Ang-2 both bind to the specific EC receptor Tie-2; however, their biologic effects are antagonistic. Ang-l binds to the Tie-2 receptor, initiating activity of the tyrosine kinase activity of this transmembrane receptor. Activation of the Tie-2 receptor leads to EC stability, and inhibits EC apoptosis. Alternatively, Ang-2 binds to the Tie-2 receptor, but antagonizes the effect of Ang-1, leading to EC destabilization and apoptosis. The coordinated induction of Ang-1, Ang-2, and VEGF has been shown to be important in the induction of tumor angiogenesis. The overall goal of this proposal is to determine the function and regulation of the angiopoietins in colon cancer angiogenesis. Specifically, we will determine: 1) the relative expression of Ang-1 and Ang-2 in human colon cancer specimens and normal mucosa. 2) the effect of over expression of the Ang-1 or Ang-2 on tumor growth, angiogenesis, and metastases in a murine model of human colon cancer. 3) the effect of over expression of Ang-l and Ang-2 on tumor permeability . 4) the effect of conditioned medium from colon cancer cells, pericytes, and non-malignant ce1ls on Ang-l and Ang-2 expression in Ecs. The significance of this pilot project is that (1) a more thorough understanding of the role of the angiopoietins in "stabilizing" and "destabilizing" the tumor neovasculature may lead to new therapeutic strategies and/or (2) may identify targets for imaging the altered neovasculature when exposed to anti-angiogenic agents.