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CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments

Oncogene volume 39, pages 2275–2289 (2020)Cite this article

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Abstract

Breast cancer is the second leading cause of cancer-related deaths for women, due mainly to metastatic disease. Invasive tumors exhibit aberrations in recruitment and activity of immune cells, including decreased cytotoxic T cells. Restoring the levels and activity of cytotoxic T cells is a promising anticancer strategy; but its success is tumor type dependent. The mechanisms that coordinate recruitment and activity of immune cells and other stromal cells in breast cancer remain poorly understood. Using the MMTV-PyVmT/FVB mammary tumor model, we demonstrate a novel role for CCL2/CCR2 chemokine signaling in tumor progression by altering the microenvironment. Selective targeting of CCR2 in the PyVmT mammary epithelium inhibited tumor growth and invasion, elevated CD8+ T cells, decreased M2 macrophages and decreased angiogenesis. Co-culture models demonstrated these stromal cell responses were mediated by tumor-derived CCL2 and CCR2-mediated suppression of the T-cell activating cytokine, CD154. Coculture analysis indicated that CCR2-induced stromal reactivity was important for tumor cell proliferation and invasion. In breast tumor tissues, CD154 expression inversely correlated with CCR2 expression and correlated with relapse free survival. Targeting the CCL2/CCR2 signaling pathway may reprogram the immune angiogenic and microenvironments and enhance effectiveness of targeted and immunotherapies.

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Fig. 1: Effect of CCR2 siRNA delivery on PyVmT mammary carcinoma growth and invasion.
Fig. 2: CCR2-deficient PyVmT mammary tumors exhibit alterations in immune cell activity and decreased angiogenesis.
Fig. 3: CCR2 knockdown enhances tumoral expression of CD154 and decreases CCL2 expression.
Fig. 4: CD154 neutralization or shRNA knockdown rescues migration but not proliferation of CCR2-deficient carcinoma cells.
Fig. 5: CCL2 shRNA knockdown inhibits migration but not proliferation of mammary carcinoma cells.
Fig. 6: Inhibition of CD154 and rescue of CCL2 expression from mammary carcinoma cells enhance recruitment and polarization of stromal cells.
Fig. 7: PyVmT mammary carcinoma cells co-cultured with macrophages show increased cell proliferation and invasion.
Fig. 8: CD154 inversely correlates with CCR2 expression and is a marker for good prognosis in invasive ductal carcinomas.

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Funding

This work was supported by funds from the American Cancer Society (RSG-13-182-01-CSM), Susan G. Komen Foundation (CCR13261859), and by the National Institutes of Health (R01CA172764) to NC.

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  1. These authors contributing equally: Gage Brummer, Wei Fang

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Gage Brummer, Wei Fang, Curtis Smart, Brandon Zinda & Nikki Cheng

  2. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Nadia Alissa & Nikki Cheng

  3. Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, 66045, USA

    Cory Berkland

  4. Department of Engineering Technology, Pittsburg State University, Pittsburg, KS, 66762, USA

    David Miller

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NC and WF are co-founders of Fennik Life Sciences, which is commercializing the TheraKanTM device.

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Written informed consent for tissue collection was obtained by the Biospecimen Core Repository according to Human Research Protection Program at the University of Kansas Medical Center (KUMC). Tissue samples were de-identified by the Biospecimen Core Repository prior to distribution. Medical records were used in compliance with KUMC and National Cancer Institute regulations. These regulations are aligned with the World Medical Association Declaration of Helsinki. Animals were maintained at KUMC in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Animal experiments were performed under an approved Institutional Animal Care and Use Committee protocol.

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Brummer, G., Fang, W., Smart, C. et al. CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments. Oncogene 39, 2275–2289 (2020). https://doi.org/10.1038/s41388-019-1141-7

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