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Epithelial CCR2 promotes breast cancer progression directly and indirectly thru crosstalk with microenvironment populations
Brummer, Gage Adam
Brummer, Gage Adam
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Abstract
Abstract The presence of immune cells within a tumor is often a good prognostic indicator, but in breast cancer the presence of tumor-promoting macrophages within the tumor predicts poor prognosis. The current model by which macrophages promote tumor progression is that tumor cells secrete chemokines to recruit the macrophages to the tumor microenvironment, which then promote vascularization and invasion of the tumor cells. The most important chemokine in this process is CCL2 (also called monocyte-chemoattract protein 1). CCL2 is a chemotactic cytokine secreted by all cell types after injury or inflammation, and by carcinoma cells. Macrophages and monocytes express CCR2, the receptor for CCL2, through which they receive this chemotactic signal. Expression of CCR2 correlates with poor prognosis and advanced disease in breast cancer. The role CCR2 expression by cancer cells is unclear, as most studies have focused on the effects of macrophage CCR2 signaling in breast cancer. These studies show that CCR2 signaling promotes tumor-cell growth and invasion directly, and indirectly by affecting the tumor microenvironment to increase CCL2 levels and decrease levels of an immune-stimulating and tumor-suppressing molecule, CD154. CCR2-expressing tumors rely on the suppression of CD154 to support the tumor-promoting macrophage phenotype. Inhibiting CCR2 signaling in tumor cells significantly alters macrophage recruitment and tumor-promoting phenotype, resulting in decreased tumor growth and invasion. Here I present a novel mechanism where tumoral CCR2 signaling orchestrates M2 macrophage polarization, angiogenesis, and suppression of CD8+ T cells to promote growth and invasion in breast cancers, with potential applications to immunotherapeutic regimens.
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Date
2019-05-31
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University of Kansas
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Keywords
Cellular biology, Immunology, Pathology, Breast, Cancer, CCR2, CD154, CD40L, macrophage