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

基本信息

批准号：
8458189
负责人：
Jessica Elizabeth Stewart Shay
金额：
$ 4.51万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458189
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 microenvironment tumor progression tumorigenesis

项目摘要

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.

描述（由适用提供）：长期以来，慢性感染一直与癌症发展的风险增加有关。例如，溃疡性结肠炎患者患结直肠癌的风险增加。在连接先天免疫系统，慢性感染和肿瘤发生时，已经暗示了与肿瘤相关的巨噬细胞（TAMS），因为患者提示较差，淋巴结介入增加和远处转移的肿瘤成层中巨噬细胞的出现。 TAM是一种异质性髓样人群，主要浸润实体瘤内缺氧区域，它们的秘密生长因子和细胞因子刺激血管生成并促进侵袭和/或转移。几项研究已经实施了氧敏感性缺氧诱导因子（HIF）转录调节剂，以控制TAM对缺氧的反应。特别是，在TAM中，HIF-2的表达升高与多种人类癌症中的预后不良和高级肿瘤相对应。巨噬细胞中HIF-2的特异性缺失可抑制与结肠炎相关结肠癌的小鼠模型中的原发性肿瘤燃烧。 HIF-2？缺乏巨噬细胞表达介导血管生成和体外侵袭的蛋白质水平。该提议的中心假设是，缺氧TAM表达促进肿瘤血管生成和转移的关键因素是需要HIF-2。从而驱动肿瘤进展。基于这一假设，我将追求两个具体的目标。具体目的1：确定髓样特异性HIF-2信号在与结肠炎相关结肠癌的炎性鼠模型中的促血管生成因子分泌中的作用。具体目的2：确定巨噬细胞中HIF-2的损失如何在结肠癌的鼠模型中最高肿瘤编程和转移。要完成这些研究，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。该提案的目的是阐明先天免疫系统中HIF-2表达的潜在机制，提高我们对缺氧如何调节感染相关癌症的理解，以及肿瘤微环境在加油肿瘤进展中起着独特的作用，从而确定新的热量靶标，从而有助于结肠癌的新疗法。