Pilot--Angiopoietins 1 & 2 in colon cancer angiogenesis

试点--血管生成素1

• 批准号: 6563962
• 负责人: LEE M. ELLIS
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563962
• 关键词: angiogenesis; angiogenesis factor; athymic mouse; clinical research; colon neoplasms; cooperative study; enzyme inhibitors; gene expression; human tissue; membrane proteins; neoplasm /cancer blood supply; neoplastic growth; vascular endothelial growth factors; vascular endothelium; vascular endothelium permeability

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.

血管生成是由导致内皮细胞(EC)的特定因素驱动的 增殖、侵袭、存活和分化。促血管生成活性 分子必须超过抗血管生成分子才能诱导 新生血管。除了诱导血管生成外，肿瘤还必须 在恶劣环境条件下(低氧或低氧)支持血管系统 PH)。为使内皮细胞在这些条件下存活，肿瘤必须分泌内皮细胞的存活。 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 欧共体的生存因素。最近，血管生成素(Ang)家族的配体已经 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 与特定的EC受体Tie-2结合；然而，它们的生物学效应是 对抗性。血管紧张素-L与Tie-2受体结合，启动血管紧张素转换酶活性 这种跨膜受体的酪氨酸激酶活性。激活 Tie-2受体能稳定内皮细胞，抑制内皮细胞凋亡。 或者，Ang-2与Tie-2受体结合，但拮抗这一作用 Ang-1的表达，导致内皮细胞失稳和细胞凋亡。协调一致的 血管紧张素-1、血管紧张素-2和血管内皮生长因子的诱导已被证明在 诱导肿瘤血管生成。 这项提案的总体目标是确定功能和 血管生成素在结肠癌血管生成中的调控。具体来说， 我们将确定： 1)Ang-1、Ang-2在结肠癌组织中的相对表达 和正常的粘膜。 2)Ang-1或Ang-2过表达对肿瘤生长的影响； 人类结肠癌小鼠模型中的血管生成和转移。 3)血管紧张素转换酶L和血管紧张素转换酶2过表达对肿瘤通透性的影响。 4)结肠癌细胞、周细胞条件培养液的作用 非恶性细胞对血管内皮细胞中血管紧张素-L和血管紧张素-2表达的影响 这个试点项目的意义在于：(1)更彻底地 对血管生成素“稳定”和“稳定”作用的认识 “破坏”肿瘤新生血管可能带来新的治疗方法 策略和/或(2)可以识别用于成像改变的目标 暴露于抗血管生成剂时的新生血管。