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（申请人提供）：作为胚胎发育的重要途径，hedgehog信号传导在干细胞维持、细胞分化和组织重塑中发挥作用。大量证据表明，hedgehog 信号传导在多种人类癌症中经常被激活。最近的几项研究表明刺猬信号在肿瘤微环境的调节中发挥着关键作用。然而，这种调节背后的分子机制在很大程度上仍然难以捉摸。我们生成的数据支持刺猬信号传导调节肿瘤免疫监视。我们发现，在缺乏刺猬蛋白介导的信号传导的情况下，骨髓源性抑制细胞（MDSC）从骨髓细胞的分化效率不高，并且刺猬蛋白信号传导的表皮特异性激活导致MDSC在脾脏、外周血和皮肤中积累。我们在该提案中的中心假设是，hedgehog 信号传导通过调节 MDSC 群体创造了一个免疫抑制环境，这与 hedgehog 信号传导介导的细胞增殖促进癌变同时发生。我们提出三个具体目标来检验我们的假设。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？ Hh 介导的 MDSC 调节。第三，我们将确定 IL-17 对于 Hh 信号介导的肿瘤发展的重要性。将 Hh 信号传导与免疫抑制性肿瘤微环境联系起来将进一步加深我们对癌症发展中 Hh 信号传导的理解，这可能有助于设计治疗和预防癌症的新策略。