A mouse model of TGFbeta1 and tumor immunosurveillance in Squamous cell cancer

描述(申请人提供)：TGFbeta1在人类癌症发展中既有肿瘤抑制作用，也有致癌作用，但这种功能变化背后的机制仍然不清楚。确定TGFbeta1这些不同功能的潜在机制以及这种变化如何发生将为癌症治疗提供重要的新靶点。我们最近开发了一种TGFbeta1条件表皮表达的小鼠模型，以确定肿瘤分期的特异性效应和TGFbeta1表达的靶点。初步研究表明，TGFbeta1在正常表皮、良性和恶性皮肤肿瘤中的表达会引起宿主免疫系统截然不同的反应，这些反应与肿瘤的消退或进展有关。这项研究建议的中心假设是，肿瘤进展过程中TGFbeta1的作用变化与免疫系统对肿瘤细胞来源的TGFbeta1的不同反应有关。特定目的1利用遗传和免疫学手段耗尽和恢复特定的免疫细胞亚群，检验对表皮来源的TGFbeta1的适应性免疫反应是阶段特异性的假设。第二个具体目的是验证这样一种假设，即在正常表皮中过度表达TGFbeta1和由此引起的炎症是对携带化学或基因激活的ras癌基因的表皮角质形成细胞的促癌刺激。特定目的3利用体外和体内生化和分子分析以及阻断NF-kappaB信号的遗传方法，在正常表皮和鳞癌中验证了NF-kappaB信号对于免疫系统对TGFbeta1的阶段特异性反应是必不可少的假说。非黑色素瘤皮肤癌在普通人群中的发病率增加，以及免疫功能低下的器官移植患者皮肤侵袭性鳞癌的问题日益严重，这是一个重大的公共卫生问题。本研究的目的是利用这种条件表达的小鼠模型来了解肿瘤细胞发育产生的TGFbeta1是如何差异化地调节抗肿瘤免疫反应的，从而最终确定能够阻断肿瘤来源的TGFbeta1的免疫抑制作用并增强其抗肿瘤炎症作用的治疗靶点和策略。

DESCRIPTION (provided by applicant): TGFbeta1 has both tumor suppressor and oncogenic roles in human cancer development, but the mechanisms underlying this change in function remain elusive. Identifying the mechanisms underlying these distinct functions of TGFbeta1 and how this change occurs will provide important new targets for cancer therapy. We have recently developed a TGFbeta1 conditional epidermal expression mouse model to identify tumor stage specific effects and targets of TGFbeta1 expression. Preliminary studies reveal that TGFbeta1 expression in the normal epidermis, benign and malignant skin tumors provokes profoundly distinct responses from the host immune system that are associated with tumor regression or progression. The central hypothesis of this research proposal is that the changing roles of TGFbeta1 during cancer progression are linked to distinct responses of the immune system to tumor cell derived TGFbeta1. Specific Aim 1 tests the hypothesis that the adaptive immune response to epidermally derived TGFbeta1 is stage specific using genetic and immunological means to deplete and restore specific immune cell subsets. The second specific aim is to test the hypothesis that overexpression of TGFbeta1 in the normal epidermis and the resulting inflammation is a tumor-promoting stimulus for epidermal keratinocytes harboring a chemically or genetically activated ras oncogene. Specific Aim 3 tests the hypothesis that NF-kappaB signaling is essential for the stage specific response of the immune system to TGFbeta1 in the normal epidermis and in squamous tumors using in vitro and in vivo biochemical and molecular analysis, and genetic methods to block NF-kappaB signaling. The increased incidence of non-melanoma skin cancer in the general population, and the increasing problem of aggressive SCC of the skin in immunocompromised organ transplant patients represent a significant public health problem. The goal of this research project are to use this conditional expression mouse model to understand how TGFbeta1 produced by developing tumor cells differentially regulates the anti-tumor immune response, so that ultimately therapeutic targets and strategies can be identified that will block the immunosuppressive effects and enhance the anti-tumor inflammatory effects of tumor derived TGFbeta1.