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

描述（由申请人提供）：成纤维细胞是肿瘤微环境的主要细胞组分，并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）直接和间接影响癌细胞行为。虽然乳腺成纤维细胞的遗传改变可能会产生促肿瘤发生作用，但对乳腺癌微环境中调节成纤维细胞功能的细胞和分子信号知之甚少。TGF-β信号的失调显著地促进转移性乳腺癌，并且还可以增强乳腺成纤维细胞中的趋化因子的表达，以促进癌症进展。基于先前的研究和初步研究，我们假设成纤维细胞中的炎性趋化因子表达，包括CCL 2和CXCL 1介导上皮细胞和免疫细胞的运动性和侵袭性，以促进乳腺癌的进展。该提案的目的是确定趋化因子的功能，这些趋化因子通常被TGF-β信号转导抑制，在乳腺癌进展过程中与肿瘤细胞的成纤维细胞相互作用。 提出了以下具体目标来解决这一假设：具体目标1：使用细胞生物学、分子和生物化学方法确定乳腺成纤维细胞中CCL 2和CXCL 1炎性趋化因子表达的机制，因为它与TGF-B信号传导有关。具体目标二：采用可移植和转基因小鼠乳腺癌模型，通过细胞生物学和生物化学方法，确定乳腺成纤维细胞表达的CCL 2和CXCL 1趋化因子在乳腺癌生长、侵袭和转移中的功能贡献。具体目标3：使用可移植小鼠癌症模型、细胞生物学和生物化学方法，确定乳腺成纤维细胞表达的CCL 2和CXCL 1趋化因子在乳腺癌进展中免疫细胞运输、归巢和募集中的作用。 具体目标1将在辅导阶段解决，而目标2和3将在辅导和独立阶段解决。这项研究将解决的功能和机制，通过成纤维细胞中的炎症趋化因子的表达有助于乳腺癌。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进展。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.