1. Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma
- Author
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Yijie Wang, Jennifer M. Curry, Ronald Glaser, Laura A. Sumner, A. Courtney DeVries, Amy C. Gross, Nisha Crouser, Jeffrey L. Voorhees, Timothy D. Eubank, Michael T. Bailey, Eric V. Yang, Kayla J. Steinberger, and Clay B. Marsh
- Subjects
Restraint, Physical ,0301 basic medicine ,Cancer Research ,Skin Neoplasms ,Transgene ,Adrenergic beta-Antagonists ,Melanoma, Experimental ,Down-Regulation ,Mice, Transgenic ,CCL2 ,Article ,Mice ,Norepinephrine ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Receptor ,Chemokine CCL2 ,Tumor microenvironment ,business.industry ,Macrophages ,Melanoma ,medicine.disease ,In vitro ,Gene Expression Regulation, Neoplastic ,Nadolol ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Catecholamine ,Immunohistochemistry ,Female ,business ,Stress, Psychological ,medicine.drug - Abstract
Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.
- Published
- 2020