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Host Cxcr2-dependent regulation of mammary tumor growth and metastasis

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Abstract

Host-derived angiogenic and inflammatory tumor supportive microenvironment regulates progression and metastasis, but the molecular mechanism(s) underlying host-tumor interactions remains unclear. Tumor expression of CXCR2 and its ligands have been shown to regulate angiogenesis, invasion, tumor growth, and metastasis. In this report, we hypothesized that host-derived Cxcr2-dependent signaling plays an important role in breast cancer growth and metastasis. Two mammary tumor cell lines Cl66 and 4T1 cells were orthotopically implanted into the mammary fat pad of wild-type and Cxcr2−/− female BALB/c mice. Tumor growth and spontaneous lung metastasis were monitored. Immunohistochemical analyses of the tumor tissues were performed to analyze proliferation, angiogenesis, apoptosis and immune cell infiltration. Our results demonstrated that knock-down of host Cxcr2 decreases tumor growth and metastasis by reducing angiogenesis, proliferation and enhancing apoptosis. Host Cxcr2 plays an important role in governing the pro-inflammatory response in mammary tumors as evaluated by decreased Gr1+ tumor-associated granulocytes, F4/80+ tumor associated macrophages, and CD11b+Gr1+ myeloid derived suppressor cells in Cxcr2−/− mice as compared to control wild-type mice. Together, these results demonstrate that host Cxcr2-dependent signaling regulates mammary tumor growth and metastasis by promoting angiogenesis and pro-inflammatory responses.

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Acknowledgements

This work was supported in part by Susan G. Komen for the Cure Grant KG090860 COBRE Grant RR021937 (Nebraska Center for Nanomedicine), and U54CA163120 and Cancer Center Support Grant (P30CA036727) from National Cancer Institute, National Institutes of Health. Bhawna Sharma was supported through University of Nebraska Medical Center Graduate Student Fellowship/Assistantship. R. K. Singh Grandly Supported by Susan G. Komen for the Cure grant KG090860.

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Authors disclose no conflict of interest.

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Authors and Affiliations

  1. Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Bhawna Sharma

  2. Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA

    Kalyan C. Nannuru

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA

    Michelle L. Varney & Rakesh K. Singh

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  1. Bhawna Sharma
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  2. Kalyan C. Nannuru
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Correspondence to Rakesh K. Singh.

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Sharma, B., Nannuru, K.C., Varney, M.L. et al. Host Cxcr2-dependent regulation of mammary tumor growth and metastasis. Clin Exp Metastasis 32, 65–72 (2015). https://doi.org/10.1007/s10585-014-9691-0

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