Myofibroblasts, T cells and malignant cells interplay in breast cancer metastasis

项目摘要 这项拟议研究的总体目标是了解癌症如何与包括癌症在内的间质相关 相关成纤维细胞(CAF)、肿瘤浸润性淋巴细胞(TIL)与癌细胞的相互作用 促进乳腺癌的肺转移。CAF和TIL在乳腺中起重要作用 肿瘤的发生和转移。 为了阐明CAF和TIL在乳腺癌肺转移中的作用，我们建立了 几种自发性和移植性乳腺肿瘤模型。我们的研究表明，该受体 活化的核因子B配体(RANKL)由肿瘤浸润性的CD4+T细胞表达，主要是Treg细胞。 肿瘤相关间质。RANKL激活其在癌细胞表面的同源受体RANK 导致IKK？的激活和核移位，进而抑制关键的转移因子maspin 抑制多种癌症的药物。然而，癌细胞、CAF和CD4+CD25+T细胞之间的联系仍然 仍然默默无闻。因此，我建议追求以下目标：从CAF中确定其他责任因素 针对Treg细胞对肿瘤的侵袭，寻找控制CAF趋化因子表达的信号通路； 检查癌细胞在成纤维细胞激活中的作用；检查替代的核因子-B途径的作用 ErbB2诱导的乳腺肿瘤中核因子-B诱导激酶(NIK)、TRAF2和TRAF3的组成 发展和转移；并识别上游成员，如果不是RANKL激活的 NIK/IKK在乳腺肿瘤发生中的作用 拟议的研究是创新的，因为它们解决了一个探索不足且有争议的研究问题。 具有重要的临床意义和公共卫生意义。

Project Summary The general goal of the proposed research is to understand how cancer associated stroma, including cancer associated fibroblast (CAF), tumor infiltrating lymphocytes (TIL) and their interactions with carcinoma cells contributes to pulmonary metastasis of breast cancer. CAF and TIL are critically involved in mammary tumorigenesis and metastasis. To address the role of CAF and TIL in pulmonary metastasis of mammary cancer, we have established several spontaneous and transplant mammary tumor models. Our research demonstrates that receptor for activated nuclear factor ¿B ligand (RANKL) is expressed by tumor infiltrating CD4+ T cells, mainly Treg cells in tumor associated stroma. RANKL activates its cognate receptor RANK on cell surface of carcinoma cells, which leads to the activation and nuclear translocation of IKK¿ and in turn the repression of maspin, a key metastasis inhibitor in a variety of cancers. However, the links between carcinoma cells, CAF, and CD4+CD25+ T cells still remain obscure. I therefore propose to pursue the following aims: Identify other factors from CAFs responsible for Treg cell infiltration into tumor; Identify signaling pathway that controls chemokine expression from CAF; Examine the role of carcinoma cells in fibroblast activation; Examine the role of alternative NF-¿B pathways components, including NF-¿B inducing kinase (NIK), TRAF2, and TRAF3 in ErbB2-induced mammary tumor development and metastasis; and identify upstream members, if other than RANKL that activates NIK/IKK¿ during mammary tumorigenesis. The proposed studies are innovative as they address a poorly explored and controversial research problem with great clinical significance and public health importance.