Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth
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Guillermo N. Armaiz-Pena1, Vianey Gonzalez-Villasana2, Archana S. Nagaraja1, Cristian Rodriguez-Aguayo2, Nouara C. Sadaoui1, Rebecca L. Stone3, Koji Matsuo4, Heather J. Dalton1, Rebecca A. Previs1, Nicholas B. Jennings1, Piotr Dorniak1, Jean M. Hansen1, Jesusa M.G. Arevalo5, Steve W. Cole5, Susan K. Lutgendorf6, Anil K. Sood1,7,8, Gabriel Lopez-Berestein2,7,8
1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
2Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
3Department of Obstetrics and Gynecology, The John Hopkins University, Baltimore, MD 21287, USA
4Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA 90089, USA
5Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, CA 90095, USA
6Department of Psychology, Obstetrics and Urology, and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
7Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
8Center for RNA Interference and Non-coding RNA, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
Gabriel Lopez-Berestein, e-mail: [email protected]
Keywords: ovarian cancer, macrophages, monocytes, catecholamines, MCP1
Received: September 15, 2014 Accepted: December 09, 2014 Published: December 27, 2014
Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production.
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