Promotion of Angiogenesis in Lung Cancer by MIF

MIF 促进肺癌血管生成

• 批准号: 6546430
• 负责人: Douglas Arenberg
• 金额: $ 26.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-18 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546430
• 关键词: SCID mouse; angiogenesis; blood vessels; cell proliferation; chemokine; clinical research; enzyme linked immunosorbent assay; flow cytometry; human tissue; immunocytochemistry; laboratory rabbit; macrophage; migration inhibition factor; molecular oncology; molecular pathology; monocyte; neoplasm /cancer blood supply; neoplastic growth; neutralizing antibody; nonsmall cell lung cancer; transfection

DESCRIPTION (provided by applicant): Angiogenesis is a central feature in both physiologic and pathophysiologic processes (repair, remodeling, tumor growth, and chronic inflammation). Research in recent years has provided evidence that cytokine "networks" operative in tumors are important in promoting angiogenesis. Elucidating the nature of these networks, while complicated, can provide important and novel insights into the biology of a tumor. Recent paradigms have suggested that tumors co-opt the host's repair and remodeling "programs" such as those used in a healing wound. This analogy is useful in that it fosters the study of tumor biology as it parallels a healing wound. An example of a feature shared between wounds and tumors is the contribution of stromal cells to the angiogenic response. We have found that macrophage migration inhibitory factor (MTF) is an important cytokine expressed by lung cancer cells in vitro which influences monocytes to express increased levels of angiogenic CXC chemokines. MIF is a cytokine discovered over 30 years ago, and has a wide array of biological effects, including immunoregulatory activity, a prominent role in lethal endotoxeinia, steroid counter-regulatory activity, and even enzymatic activity. Recent evidence has suggested a role for MIF in regulating tumor growth and angiogenesis. However, our data suggest that MIF promotes angiogenesis indirectly, without any evidence of direct angiogenic activity of MIF in vitro. This proposal will more strictly define the mechanism by which MIF promotes tumor angiogenesis in vivo, and to correlate these findings with actual human tumors resected from patients with lung cancer. Among the questions to be addressed are; 1) Does inhibition of MIF in an animal model reduce CXC chemokine-dependent angiogenic activity, and does overexpression of MIF in vivo promote CXC chemokine dependent angiogenic activity? (i.e. Is MIF necessary and sufficient for inducing CXC chernokine dependent activity from infiltrating monocytes?) 2) Does MIF correlate with vascularity of human tumors? 3) Does MIF correlate with levels of angiogenic CXC chemokines in human tumors? 4) Does high expression of MIF predict poor clinical outcomes?

描述（由申请人提供）：血管生成是生理和病理生理过程（修复、重塑、肿瘤生长和慢性炎症）的核心特征。近年来的研究提供的证据表明，在肿瘤中起作用的细胞因子“网络”对于促进血管生成很重要。阐明这些网络的性质虽然很复杂，但可以为肿瘤生物学提供重要而新颖的见解。最近的范例表明，肿瘤选择了宿主的修复和重塑“程序”，例如用于愈合伤口的程序。这个类比是有用的，因为它促进了肿瘤生物学的研究，因为它与正在愈合的伤口相似。伤口和肿瘤之间共有特征的一个例子是基质细胞对血管生成反应的贡献。我们发现巨噬细胞迁移抑制因子（MTF）是肺癌细胞在体外表达的重要细胞因子，它影响单核细胞表达增加水平的血管生成CXC趋化因子。 MIF 是 30 多年前发现的一种细胞因子，具有广泛的生物效应，包括免疫调节活性、在致死性内毒素血症中的重要作用、类固醇反调节活性，甚至酶活性。最近的证据表明 MIF 在调节肿瘤生长和血管生成中发挥作用。然而，我们的数据表明，MIF 间接促进血管生成，但没有任何证据表明 MIF 在体外具有直接血管生成活性。该提案将更严格地定义MIF促进体内肿瘤血管生成的机制，并将这些发现与从肺癌患者身上切除的实际人类肿瘤相关联。要解决的问题包括： 1) 在动物模型中抑制 MIF 是否会降低 CXC 趋化因子依赖性血管生成活性，体内 MIF 的过度表达是否会促进 CXC 趋化因子依赖性血管生成活性？ （即，MIF 对于诱导浸润单核细胞的 CXC 趋化因子依赖性活性是否是必要且充分的？） 2) MIF 是否与人类肿瘤的血管分布相关？ 3) MIF 与人类肿瘤中血管生成 CXC 趋化因子的水平相关吗？ 4) MIF 高表达是否预示临床结果不佳？