Regulation of immune surveillance by hedgehog signaling in tumor microenvironment

肿瘤微环境中刺猬信号调节免疫监视

基本信息

批准号：
8515974
负责人：
JINGWU XIE
金额：
$ 30.43万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515974
关键词：
Affect Bone Marrow Cells Cancer Biology Cancer Center Cell Differentiation process Cell Maintenance Cell Proliferation Cells Data Defect Development Embryonic Development Environment Epidermis Erinaceidae Exhibits Fibroblasts Generations Genetic Goals Hematopoiesis Human Immune Immunologic Surveillance Immunology Immunosuppression In Situ Inflammatory Interleukin-17 Laboratories Langerhans cell Lead Link Malignant Neoplasms Mediating Modeling Molecular Mus Myelogenous Pathway interactions Play Population Regulation Research Role Signal Transduction Site Skin Skin Neoplasms Source Spleen Stem cells Suppressor-Effector T-Lymphocytes T-Lymphocyte Testing Therapeutic Tissues Work base cancer prevention carcinogenesis cell motility chemokine cytokine design innovation melanocyte mortality neoplastic cell novel novel strategies peripheral blood prevent progenitor smoothened signaling pathway tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): As an important pathway in embryonic development, hedgehog signaling plays a role in stem cell maintenance, cell differentiation and tissue remodeling. Amounting evidence indicate that hedgehog signaling is frequently activated in a variety of human cancer. Several recent studies indicate a critical role of hedgehog signaling in regulation of tumor microenvironment. The molecular mechanisms underlying this regulation, however, remain largely elusive. We have generated data to support that hedgehog signaling regulates tumor immune surveillance. We showed that myeloid-derived suppressor cells (MDSC) differentiation from bone marrow cells in the absence of hedgehog-mediated signaling was not efficient, and that epidermis-specific activation of hedgehog signaling yielded accumulation of MDSC in spleen, peripheral blood and skin. Our central hypothesis in this proposal is that hedgehog signaling creates an immune suppressive environment through regulation of MDSC population, which is in parallel with hedgehog signaling-mediated cell proliferation that promotes carcinogenesis. We propose three specific aims to test our hypothesis. First, we will define how Hh signaling regulates MDSC formation. Second, we will identify the critical role of TGF? in Hh-mediated regulation of MDSC. Third, we will determine the significance of IL-17 for Hh signaling-mediated tumor development. Linking Hh signaling to the immune suppressive tumor microenvironment will further our understanding of Hh signaling in cancer development, which may permit the design of novel strategies for the treatment and prevention of cancer.

描述（由申请人提供）：作为胚胎发育的重要途径，刺猬信号在干细胞维持，细胞分化和组织重塑中起作用。大量证据表明，刺猬信号在各种人类癌症中经常被激活。最近的一些研究表明，刺猬信号在调节肿瘤微环境中的关键作用。然而，该调节的基本机制仍然难以捉摸。我们已经生成数据来支持刺猬信号传导调节肿瘤免疫监测。我们表明，在没有刺猬介导的信号传导的情况下，髓样衍生的抑制细胞（MDSC）从骨髓细胞中分化并不有效，并且表皮特异性激活刺猬信号导致MDSC在脾，外周血和皮肤中的MDSC积累。我们在该提案中的中心假设是，刺猬信号传导通过调节MDSC种群创造了免疫抑制环境，MDSC人群与刺猬信号介导的细胞增殖相似，从而促进致癌。我们提出了三个特定的目的来检验我们的假设。首先，我们将定义HH信号如何调节MDSC形成。其次，我们将确定TGF的关键作用？在HH介导的MDSC调节中。第三，我们将确定IL-17对HH信号介导的肿瘤发育的重要性。将HH信号与免疫抑制性肿瘤微环境联系起来将进一步了解我们对癌症发育中HH信号传导的理解，这可能允许设计用于治疗和预防癌症的新型策略。