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

描述(申请人提供)：拟议研究的总体目标是了解癌症相关间质，包括癌症相关成纤维细胞(CAF)、肿瘤浸润性淋巴细胞(TIL)及其与癌细胞的相互作用如何促进乳腺癌的肺转移。CAF和TIL在乳腺肿瘤的发生和转移中起重要作用。 为了探讨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，活化核因子B配体受体(RANKL)由肿瘤浸润性的CD4+T细胞表达，主要是肿瘤相关间质中的Treg细胞。RANKL激活肿瘤细胞表面的同源受体RANK，导致Ikka的激活和核转位，进而抑制多种癌症中的关键转移抑制因子maspin。然而，癌细胞、CAF和CD4+CD25+T细胞之间的联系仍然不清楚。因此，我建议追求以下目标：从CAF中找出导致Treg细胞向肿瘤中渗透的其他因素；从CAF中找出控制趋化因子表达的信号通路；研究癌细胞在成纤维细胞激活中的作用；研究替代的NF-B通路成分，包括核因子-B诱导激酶(NIK)、TRAF2和TRAF3在ErbB2诱导的乳腺肿瘤发生和转移中的作用；以及确定上游成员，如果不是RANKL，在乳腺肿瘤发生过程中激活NIK/Ikka。 拟议的研究具有创新性，因为它们解决了一个探索不足、具有重大临床意义和公共卫生重要性的有争议的研究问题。 公共卫生相关性：乳腺癌是美国女性第二常见的恶性肿瘤，也是与癌症相关的死亡的主要原因，主要是由于晚期肿瘤转移到骨、肺、脑和肝脏造成的。这项建议将重点放在肿瘤相关吻合口(主要是CAF)与肿瘤浸润性T细胞和癌细胞之间的相互作用。这项拟议的研究将有助于理解炎症信号在肺转移中的基础作用，并揭示潜在的重要靶点，从而治愈乳腺癌转移。

DESCRIPTION (provided by applicant): 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 IKKa 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/IKKa 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. PUBLIC HEALTH RELEVANCE: Breast cancer is second common malignancy and the leading cause of cancer-related mortality amongst women in the US, mainly caused by metastatic spread of advanced tumors to bone, lung, brain and liver. This proposal will focus on the interplays between tumor associated stoma, mainly CAFs, and tumor-infiltrating T cells and carcinoma cells. This proposed study should shed light on the understanding of fundamental role of inflammatory signals in pulmonary metastasis and reveal potential targets of great importance leading to the cure for mammary cancer metastasis.