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（申请人提供）：肿瘤缺氧促进对放疗和化疗的抵抗，并选择高度恶性细胞的出现。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因子，并且HIF高表达。在许多人类癌症中，HIF 通过促进癌细胞的生长、代谢和存活以及调节招募和功能来促进肿瘤进展和转移。因此，HIF 被认为是一种有吸引力的治疗靶点，并且人们一直致力于鉴定用于癌症治疗的 HIF 抑制剂，然而，由于最近对不同的 HIF 复合物的研究，这种方法的基本原理已引起争议。显示在不同的细胞环境中促进或抑制肿瘤生长和进展大多数 HIF 反应是由含有 HIF-1¿ 的两个独立的转录复合物介导的。或 HIF-2¿ ，每个都结合组成型表达的亚基 ARNT（也称为 HIF-1¿），尽管它们履行一些冗余功能，但 HIF-1¿和 HIF-2¿迄今为止，基因工程小鼠癌症模型已经研究了仅删除 HIF-1 的影响。或 HIF-2¿独立地，不评估剩余 HIF-¿ 的功能重要性经检查，HIF 亚单位可能促进或抑制肿瘤进展，但无法准确预测癌细胞和相关基质细胞中完全缺乏 HIF 的影响，并可能导致特定情况下意外的肿瘤进展。我们将使用组织特异性 Cre 表达来删除 Arnt/Hif-1¿小鼠结肠癌细胞和肿瘤相关巨噬细胞 (TAM) 中的基因（以及 HIF-1¿ 和 HIF-2¿ 功能）这种方法将首次模拟泛 HIF 抑制对本地小鼠的影响。这项工作还将为开发药理学 HIF 抑制剂作为安全有效的癌症疗法的持续努力提供信息。