Project 2: 2/2 The Alabama State University/UAB Comprehensive Cancer Center Partnership

项目总结：前列腺癌（PCa）是最常见的非皮肤恶性肿瘤，也是第二大癌症 美国男性死亡的原因既往使用PCa动物模型和人类进行的研究 证明前列腺产生多种生长因子。添加或阻断这些因子可改变PCa细胞 扩散等功能。在这些因子中，转化生长因子-β1（TGF-β 1）参与了 肿瘤发生性，显示出有效的免疫抑制活性，并且是常规CD 4+转化所必需的。 T细胞转化为FoxP 3+调节性T（TR）细胞。表达转录因子Foxp 3的TR细胞对于正常的 免疫功能; TR细胞的缺乏导致多器官自身免疫和死亡。TGF-β及其受体的明确作用 在PCa发展和进展过程中对TR的影响缺乏实验证据。 在这项提议中，我们计划使用以下方法研究TGF-β和/或TR的潜在机制： 在C57/B6小鼠中，来自前列腺癌转基因小鼠（TRAMP）的PCa细胞系。在这些细胞系中， TRAMP-C1和TRAMP-C2形成肿瘤; TRAMP-C3不能这样做。这些小鼠PCa细胞系可用于 获得这个项目的长期目标，这是解决根本问题：TR细胞和/或TGF-β 水平与TRAMP细胞系（C1，C2和C3）的致瘤性差异有关？本项目的目标是 为了确定宿主细胞产生TGF-β对TRAMP细胞系的反应或TRAMP细胞系表达TGF-β的作用， 建立TGF-β对幼稚CD 4 + T细胞转化为表达Foxp 3的TR细胞的功能。

Project summary: Prostate cancer (PCa) is the most common non-skin malignancy and the cancer second most responsible for death in men in United States. Prior studies with animal models of PCa and with humans demonstrated that the prostate produces various growth factors. Addition or blocking of these factors alters PCa cell proliferation and other functions. Among these factors, transforming growth factor-β1 (TGF-β) is involved in tumorigenicity, displays potent immunosuppressive activities, and is required for the conversion of conventional CD4+ T cells to FoxP3+ regulatory T (TR) cells. TR cells that express the transcription factor Foxp3 are essential for normal immune function; absence of TR cells results in multi-organ autoimmunity and death. A clear role of TGF-β and its effect on TR during PCa development and progression lacks experimental evidence. In this proposal, we plan to investigate the underlying mechanisms involved in the context of TGF-β and/or TR using PCa cell lines, derived from transgenic mouse for prostate cancer (TRAMP), in C57/B6 mice. Of these cell lines, TRAMP- C1 and TRAMP-C2 form tumors; TRAMP-C3 fails to do so. These mouse cell lines of PCa can be used to obtain the long-term goal of this project, which is to address the fundamental question: Do TR cells and/or TGF-β levels relate to differences in tumorigenicity of the TRAMP cell lines (C1, C2, and C3)? The objective of this project is to define the role of TGF-β production by host cells in response to or TGF-β expression by TRAMP cell lines and to establish the function of TGF-β on the conversion of naive CD4+ T cells into Foxp3-expressing TR cells.