American Association for Cancer Research
19406207capr190370-sup-226372_2_supp_6302666_q6jh6b.docx (126.96 kB)

Supplementary Figure 4 from Stress-induced Norepinephrine Downregulates CCL2 in Macrophages to Suppress Tumor Growth in a Model of Malignant Melanoma

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journal contribution
posted on 2023-04-03, 22:00 authored by Kayla J. Steinberger, Michael T. Bailey, Amy C. Gross, Laura A. Sumner, Jeffrey L. Voorhees, Nisha Crouser, Jennifer M. Curry, Yijie Wang, A. Courtney DeVries, Clay B. Marsh, Ronald Glaser, Eric V. Yang, Timothy D. Eubank

Neither norepinephrine nor recombinant CCL2 have proliferative effects on B16F10 cells.




Gilbert and Kathryn Mitchell Endowment

Research Investment Fund

OSU College of Medicine

OSU Comprehensive Cancer Center Core



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.

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