Hypoxia and HIF in Tumor-Associated Macrophage Driven Tumor Progression

肿瘤相关巨噬细胞驱动的肿瘤进展中的缺氧和 HIF

• 批准号: 8312983
• 负责人: Jessica Elizabeth Stewart Shay
• 金额: $ 4.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312983
• 关键词: Angiogenic Factor; Animal Model; Appearance; Behavior; Biochemistry; Bone Marrow; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chronic; Coculture Techniques; Colitis; Colon Carcinoma; Colorectal Cancer; Conditioned Culture Media; Data; Development; Distant Metastasis; Endothelial Cells; Exposure to; Genetic; Genetic Transcription; Growth Factor; Human; Hypoxia; Hypoxia Inducible Factor; Image; Immune system; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Knock-out; Life; Lymph Node Involvement; Malignant Neoplasms; Mediating; Methods; Modeling; Monitor; Mus; Myelogenous; Neoplasm Metastasis; Oxygen; Patients; Persons; Play; Population; Primary Neoplasm; Proteins; Radiosurgery; Risk; Role; Signal Transduction; Solid Neoplasm; Testing; Tube; Tumor Angiogenesis; Tumor Burden; Tumor Cell Invasion; Ulcerative Colitis; United States; Vascular Endothelial Cell; angiogenesis; bHLH-PAS factor HLF; base; cancer risk; cell transformation; chemotherapy; cytokine; hypoxia inducible factor 1; improved; in vitro Assay; in vivo; insight; macrophage; migration; mouse model; neoplastic cell; neovascularization; new therapeutic target; outcome forecast; research study; response; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Chronic inflammation has long been associated with increased risk of cancer development. For example, patients with ulcerative colitis have an increased risk of developing colorectal cancer. Tumor-associated macrophages (TAMs) have been implicated in connecting the innate immune system, chronic inflammation and tumorigenesis, as the appearance of macrophages in tumors corelates with poor patient prognosis, increased lymph node involvement, and distant metastases. TAMs are a heterogeneous myeloid population that infiltrates predominantly hypoxic regions within solid tumors, where they secrete growth factors and cytokines that stimulate angiogenesis and facilitate invasion and/or metastasis. Several studies have implicated the oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators in controlling TAM response to hypoxia. In particular, elevated expression of HIF-2¿ in TAMs corresponds with poor prognosis and high-grade tumors in a variety of human cancers. Specific deletion of HIF-2¿ in macrophages suppresses primary tumor burden in a mouse model of colitis-associated colon carcinoma. HIF-2¿ deficient macrophages express reduced levels of proteins mediating angiogenesis and invasion in vitro. The central hypothesis of this proposal is that HIF-2¿ is required for hypoxic TAMs to express critical factors that promote tumor angiogenesis and metastasis, and thereby drive tumor progression. Based on this hypothesis, I will pursue two specific aims. Specific Aim 1: To determine the role of myeloid-specific HIF-2¿ signaling in the secretion of pro-angiogenic factors in an inflammatory murine model of colitis-associated colon cancer. Specific Aim 2: To determine how loss of HIF-2¿ in macrophages supreses tumor progresion and metastasis in a murine model of colon cancer. To complete these studies I will combine in vitro and in vivo methods of cell biology, biochemistry, immunohistochemistry, live imaging, genetics, and animal modeling. The objective of this proposal is to elucidate the underlying mechanisms of HIF-2¿ expression in the innate immune system, improve our understanding of how hypoxia regulates inflammation-associated cancer, and the unique role tumor microenvironment plays in fueling tumor progression and thereby identify novel therapeutic targets which will facilitate new treatments for colon cancer. PUBLIC HEALTH RELEVANCE: Colorectal cancer (CRC) is one of the leading causes of death in the United States with available treatments consisting of surgery, radiation, and chemotherapy. Certain states of chronic inflammation can increase a person's risk of developing CRC and although there is very convincing evidence that inflammation plays a direct role in tumor progression, the underlying mechanisms are not fully elucidated. I therefore propose to investigate the relationship between chronic inflammation and cancer development in order to facilitate the identification and advancement of novel therapeutic targets.

描述（由申请人提供）：长期以来，慢性炎症与癌症发生的风险增加有关，例如，溃疡性结肠炎患者患结直肠癌的风险增加，与先天性连接有关。免疫系统、慢性炎症和肿瘤发生，因为肿瘤中巨噬细胞的出现与患者预后不良、淋巴结受累增加和远处转移有关。浸润实体瘤内主要缺氧区域的异质性骨髓细胞群，在那里它们分泌刺激血管生成并促进侵袭和/或转移的生长因子和细胞因子，一些研究表明氧敏感的缺氧诱导因子（HIF）转录调节因子在控制TAM反应中。特别是 HIF-2 表达升高。 TAM 中的 HIF-2 特异性缺失与多种人类癌症的不良预后和高级别肿瘤相对应。巨噬细胞抑制结肠炎相关结肠癌小鼠模型中的原发性肿瘤负荷。缺乏的巨噬细胞在体外表达介导血管生成和侵袭的蛋白质水平降低。该提议的中心假设是 HIF-2¿缺氧 TAM 需要表达促进肿瘤血管生成和转移的关键因子，从而驱动肿瘤进展。基于这一假设，我将追求两个具体目标 1：确定骨髓特异性 HIF-2 的作用。结肠炎相关结肠癌炎症小鼠模型中促血管生成因子分泌中的信号传导 具体目标 2：确定 HIF-2 的缺失是如何发生的。为了完成这些研究，我将结合细胞生物学、生物化学、免疫组织化学、实时成像、遗传学和动物建模的体外和体内方法。目的是阐明 HIF-2 的潜在机制？其在先天免疫系统中的表达，提高我们对缺氧如何调节炎症相关癌症的理解，以及肿瘤微环境在促进肿瘤进展中发挥的独特作用，从而确定新的治疗靶点，从而促进结肠癌的新治疗。 公共健康相关性：结直肠癌 (CRC) 是美国主要的死亡原因之一，可用的治疗方法包括手术、放疗和化疗。某些慢性炎症状态会增加人患结直肠癌的风险。尽管有非常令人信服的证据表明炎症在肿瘤进展中起着直接作用，但其潜在机制尚未完全阐明，因此我建议研究慢性炎症与癌症发展之间的关系，以促进新治疗靶点的识别和发展。