Combined HIF deficiency in inflammation-associated colorectal tumorigenesis

炎症相关结直肠肿瘤发生中联合 HIF 缺乏

基本信息

批准号：
8838847
负责人：
M. CELESTE SIMON
金额：
$ 39.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838847
关键词：
ARNT gene Ablation Alleles Binding Biological Biological Assay Blood Vessels Bone Marrow Breeding Cancer Model Cell Proliferation Cell division Cell physiology Colitis Colon Carcinoma Colorectal Cancer Complex Data Environment Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Engineering Genomics Growth Health Human Hypoxia Hypoxia Inducible Factor Immune response In Vitro Inflammation Investigation Knockout Mice Light Malignant Epithelial Cell Malignant Neoplasms Mediating Metabolism Modeling Molecular Mouse Strains Mus Myeloid Cells Neoplasm Metastasis Oncogene Proteins Oxygen Pharmaceutical Preparations Proteins Publishing Radiation therapy Relative (related person)Reporting Resistance Role Stem cells Stromal Cells Testing The Cancer Genome Atlas Time Tissues Tumor Biology Tumor Suppressor Proteins Work angiogenesis bHLH-PAS factor HLF c-myc Genes cancer cell cancer therapy chemotherapy colon cancer patients colon tumorigenesis design human data hypoxia inducible factor 1 in vivo inhibitor/antagonist insight macrophage migration mouse model neoplastic cell novel overexpression pre-clinical research study response therapeutic target time use tumor tumor growth tumor metabolism tumor progression villin

项目摘要

DESCRIPTION (provided by applicant): Tumor hypoxia promotes resistance to radiotherapy and chemotherapy, and selects for the emergence of highly malignant cells. The Hypoxia Inducible Factors (HIFs) are the primary transcriptional regulators mediating cellular adaptation to tissue hypoxia, and HIFs are highly expressed in many human cancers. HIFs contribute to tumor progression and metastasis by promoting the growth, metabolism, and survival of cancer cells, as well as modulating the recruitment and function of tumor-associated stromal cells. HIFs have therefore been proposed as an attractive therapeutic target, and significant effort has been focused on identifying HIF inhibitors for cancer therapy. The rationale for this approach has become controversial, however, as distinct HIF complexes have been recently shown to either promote or suppress tumor growth and progression in different cellular contexts. The majority of HIF responses are mediated by two independent transcriptional complexes containing either HIF-1¿ or HIF-2¿, each of which binds the constitutively expressed subunit ARNT (also called HIF-1¿). Although they fulfill some redundant functions, HIF-1¿ and HIF-2¿ also antagonize each other's effects on tumor metabolism, angiogenesis, and immune responses. To date, genetically engineered murine cancer models have investigated the effects of deleting only HIF-1¿ or HIF-2¿ independently, without assessing the functional importance of the remaining HIF-¿ subunit, which may act to either promote or suppress tumor progression. Consequently, the impact of full HIF-deficiency in cancer cells and associated stromal cells cannot be accurately predicted, and could result in unintended tumor progression in specific settings. In this proposal, we will use tissue-specific Cre expression to delete the Arnt/Hif-1¿ gene (and both HIF-1¿ and HIF-2¿ function) in murine colon carcinoma cells and tumor-associated macrophages (TAMs). This approach will, for the first time, model the impact of pan-HIF inhibition in an autochthonous murine tumor model. This work will also inform ongoing efforts to develop pharmacological HIF inhibitors as safe and effective cancer therapies.

描述（由应用提供）：肿瘤缺氧促进了对放射疗法和化学疗法的耐药性，并为高度恶性细胞的出现选择。缺氧诱导因子（HIF）是介导细胞适应组织缺氧的主要转录调节剂，而HIF在许多人类癌症中都高度表达。 HIF通过促进癌细胞的生长，代谢和存活以及调节与肿瘤相关的基质细胞的募集和功能来促进肿瘤进展和转移。因此，HIF被认为是一个有吸引力的治疗靶标，并且重大的努力集中在鉴定HIF抑制剂以进行癌症治疗。但是，由于最近已显示出不同的HIF复合物可以促进或抑制不同细胞环境中肿瘤的生长和进展，因此这种方法的理由已成为有争议的。大多数HIF响应是由包含HIF-1或HIF-2¿的两个独立的转录复合物介导的，每个复合物都结合了组成型表达的亚基ARNT（也称为HIF-1。）。尽管他们履行了一些冗余功能，但HIF-1¿和HIF-2¿也会拮抗彼此对肿瘤代谢，血管生成和免疫复杂的影响。迄今为止，基因工程的鼠类癌模型已经独立研究了仅删除HIF-1或HIF-2的效果，而无需评估其余HIF-®亚基的功能重要性，这些功能可以促进或抑制肿瘤进展。因此，无法准确预测癌细胞和相关基质细胞中全HIF缺乏症的影响，并且可能导致特定环境中意外的肿瘤进展。在此提案中，我们将使用组织特异性的CRE表达来删除鼠结肠癌细胞和肿瘤相关巨噬细胞（TAMS）中删除ARNT/HIF-1基因（以及HIF-1和HIF-1功能）。这种方法将首次建模泛HIF抑制在自毒鼠肿瘤模型中的影响。这项工作还将为开发HIF抑制剂作为安全有效的癌症疗法而进行的持续努力。