Molecular mechanisms of host-derived CCL5 mediated mammary tumor growth

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DESCRIPTION (provided by applicant): Breast cancer is the most common type of malignant tumor among women in North America. Higher CCL5 production in breast cancer patients is associated with more progressive disease, indicating an important role of CCL5 in breast cancer progression. Recently, we have found that CCL5 deficient mice are highly resistant to mammary tumor growth and metastasis, with decreased numbers of macrophages infiltrated in the tumor. Therefore, we hypothesize that host CCL5 promotes mammary gland tumor progression by attracting macrophages migrated into the tumor. Blocking CCL5 signaling in a tumor-bearing host may serve as a new therapeutic target for breast cancer treatments. CCL5 is a chemokine produced by a variety of cells, including T cells, macrophages, fibroblasts and tumor cells. It plays an important role in inflammation by recruiting T cells, macrophages and eosinophils to inflammatory sites. CCL5 has been shown to be able to help in tumor angiogenesis, inhibit T cell responses and enhance growth of breast cancers. Using a syngeneic mammary tumor model, a recent study demonstrates that tumor-derived CCL5 is dispensable for tumor progression, suggesting it is the host-derived CCL5 which is important for breast cancer growth and metastasis. Our preliminary data demonstrates that mice genetically deficient in CCL5 (CCL5-KO) are resistant to tumor-induced death and develop few lung metastases. Consistent with these findings, neutralization of CCL5 in wild-type mice suppresses tumor growth and lung metastases. Further analyses of tumors by flow cytometry and immunofluorescence staining reveal a significant decrease of macrophages in the tumors of CCL5-KO mice. Our data provides direct evidence for the first time that host-derived CCL5 is essential for mammary tumor growth and metastasis. Since the mechanisms of host-derived CCL5 in promoting mammary tumor progression are largely unknown, we propose to investigate the mechanisms whereby host-derived CCL5 mediates macrophage infiltration into the tumors and the molecular mechanisms by which tumor cells induce CCL5 expression in host macrophages. Our long-term goal is to elucidate the cellular, molecular and immunologic mechanisms by which host CCL5 promotes breast cancer growth and metastasis, and to ultimately develop therapeutic agents that target CCL5 in a tumor-specific manner. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common type of malignant tumor among women in North America. Higher CCL5 production in breast cancer patients is associated with more progressive disease, indicating an important role of CCL5 in breast cancer progression. Our goal is to elucidate the cellular, molecular and immunologic mechanisms by which host CCL5 promotes breast cancer growth and metastasis, and to ultimately develop therapeutic agents that target CCL5 in a tumor-specific manner.