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

项目摘要 拟议研究的总体目标是了解癌症如何与基质相关，包括癌症 相关成纤维细胞（CAF）、肿瘤浸润淋巴细胞（TIL）及其与癌细胞的相互作用 有助于乳腺癌的肺转移。CAF和TIL在乳腺癌的发生发展中起重要作用。 肿瘤发生和转移。 为了探讨CAF和TIL在乳腺癌肺转移中的作用，我们建立了CAF和TIL在乳腺癌肺转移中的表达。 几种自发和移植乳腺肿瘤模型。我们的研究表明， 活化的核因子B配体（RANKL）由肿瘤浸润性CD 4 + T细胞表达，主要是肿瘤浸润性T细胞中的Treg细胞。 肿瘤相关间质。RANKL激活癌细胞表面的同源受体RANK， 导致IKK的激活和核转位，进而抑制maspin，一种关键的转移 在多种癌症中的抑制剂。然而，癌细胞、CAF和CD 4 + CD 25 + T细胞之间的联系仍然存在。 保持模糊。因此，我建议追求以下目标： 鉴定控制CAF趋化因子表达的信号通路; 检查癌细胞在成纤维细胞活化中的作用;检查替代NF-B途径的作用 在ErbB 2诱导的乳腺肿瘤中，包括NF-B诱导激酶（NIK）、TRAF 2和TRAF 3 发展和转移;并确定上游成员，如果不是RANKL，激活 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和有争议的研究问题 具有重要的临床意义和公共卫生重要性。

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.