Functions of chemokine and TGF-B signaling in the breast cancer microenvironment

描述(申请人提供)：成纤维细胞是肿瘤微环境的主要细胞成分，通过分泌可溶性因子，包括生长调节剂、血管生成因子和趋化因子，直接或间接地影响癌细胞的行为。虽然乳腺成纤维细胞的基因改变可能会发挥促肿瘤作用，但对调控乳腺癌微环境中成纤维细胞功能的细胞和分子信号知之甚少。转化生长因子-β信号的失控显著促进了转移性乳腺癌的发生，也可能增强了乳腺成纤维细胞中趋化因子的表达，从而促进了肿瘤的进展。在前人研究和初步研究的基础上，我们假设包括CCL2和CXCL1在内的成纤维细胞中炎性趋化因子的表达介导了上皮细胞和免疫细胞的运动和侵袭，从而促进了乳腺癌的进展。这项建议的目的是确定在乳腺癌进展过程中成纤维细胞与肿瘤细胞相互作用中趋化因子的功能，这些趋化因子通常被转化生长因子-β信号抑制。 具体目标1：利用细胞生物学、分子生物学和生物化学方法，研究乳腺成纤维细胞中CCL2和CXCL1炎性趋化因子的表达及其与转化生长因子-β信号转导的关系。具体目的2：通过建立可移植和转基因小鼠乳腺癌模型，采用细胞生物学和生化方法，研究乳腺成纤维细胞表达的趋化因子CCL2和CXCL1在乳腺癌生长、侵袭和转移中的作用。具体目的3：利用可移植的小鼠肿瘤模型、细胞生物学和生化方法，确定乳腺成纤维细胞表达的CCL2和CXCL1趋化因子在乳腺癌进展过程中免疫细胞的运输、归巢和募集中的作用。 具体目标1将在指导阶段解决，而目标2和目标3将在指导和独立阶段解决。本研究将探讨成纤维细胞中炎性趋化因子表达在乳腺癌发生中的作用和机制。通过这些研究，我们试图进一步了解基质细胞在宿主微环境中的功能，以及宿主微环境如何在分子、细胞和体内水平上促进肿瘤的发展。通过进一步了解肿瘤微环境在癌症进展中的作用，将有可能确定新的治疗分子靶点，并开发诊断和治疗转移性乳腺癌的改进方法。

DESCRIPTION (provided by applicant): Fibroblasts are a major cellular component of the tumor microenvironment and influence cancer cell behavior directly and indirectly through secretion of soluble factors, including growth regulators, angiogenic factors and chemokines. While genetic alterations in breast fibroblasts may exert pro-tumorigenic effects, little is known of the cellular and molecular signals that regulate fibroblast functions in the breast cancer microenvironment. De-regulation of TGF-B signaling significantly contributes to metastatic breast cancer, and may also enhance expression of chemokines in breast fibroblasts, to promote cancer progression. Based on previous studies and preliminary studies, we hypothesize that inflammatory chemokine expression in fibroblasts including CCL2 and CXCL1 mediate epithelial cell and immune cell motility and invasiveness to promote breast cancer progression. The objective of this proposal is determine the functions of chemokines, which are normally suppressed by TGF-B signaling, in fibroblast interactions with tumor cells during breast cancer progression. The following Specific Aims are proposed to address this hypothesis: Specific Aim 1: To determine the mechanisms of CCL2 and CXCL1 inflammatory chemokine expression in mammary fibroblasts as it relates to TGF-B signaling using cell biology, molecular and biochemical approaches. Specific Aim 2: To determine the functional contribution of CCL2 and CXCL1 chemokines expressed by mammary fibroblasts in breast cancer growth, invasion and metastasis, using transplantable and transgenic mouse models of breast cancer, cell biological and biochemical approaches. Specific Aim 3 : To determine the contribution of CCL2 and CXCL1 chemokines expressed by mammary fibroblasts in immune cell trafficking, homing and recruitment in breast cancer progression using transplantable mouse models of cancer, cell biological and biochemical approaches. Specific Aim 1 would be addressed during the mentored phase, while Aims 2 and 3 would be addressed during the mentored and independence phases. This research will address the functions and mechanisms through which inflammatory chemokine expression in fibroblasts contributes to breast cancer. Through these studies, we seek to further understand the functions of stromal cells in the host microenvironment, and how the host microenvironment contributes to tumor progression at the molecular, cellular and in vivo levels. By further understanding the role of the tumor microenvironment in cancer progression, it will be possible to identify new molecular targets for therapy and to develop improved methods for diagnosing and treating metastatic breast cancer.