Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth.

Guillermo N Armaiz-Pena,Koji Matsuo,Rebecca A Previs,Cristian Rodriguez-Aguayo,Piotr Dorniak,Susan K Lutgendorf,Archana S Nagaraja,Gabriel Lopez-Berestein,Anil K Sood,Steve W Cole,Rebecca L Stone,Nouara C Sadaoui,Jean M Hansen,Heather J Dalton,Vianey Gonzalez-Villasana,Jesusa M.G Arevalo,Nicholas B Jennings

doi:10.18632/oncotarget.2887

Abstract

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.

Highlights

Sustained adrenergic activation resulting from prolonged behavioral stress leads to increased tumor growth [1, 2]
To elucidate the mechanism used by tumor cells to induce monocyte/macrophage recruitment while undergoing sustained adrenergic signaling, we analyzed chemokine/cytokine changes using a cytokine/chemokine panel generated from SKOV3ip1 cells treated with norepinephrine or epinephrine
We demonstrate that increased adrenergic signaling leads to enhanced macrophage recruitment, which is mediated by tumor cell-derived MCP1

Summary

Introduction

Sustained adrenergic activation resulting from prolonged behavioral stress leads to increased tumor growth [1, 2]. Sympathetic nervous system activity directly influences the pathogenesis of ovarian carcinoma by protecting tumor cells from anoikis [4], promoting tumor cell invasion [5,6,7] and increasing tumor-associated angiogenesis [1, 8] These data highlight the importance of the tumor microenvironment in these processes, but the underlying mechanisms require further analysis. Tumor associated macrophages (TAMs) are key components of the tumor microenvironment [9] and reflect www.impactjournals.com/oncotarget a continuum of maturation/differentiation of bone marrow derived monocyte precursors that adapt to the different microenvironments where they will eventually reside [10] They differentiate from circulating blood monocytes recruited into the tumor microenvironment and are rapidly activated by tumor cells. We demonstrate that increased peripheral blood monocytes and TAMs are associated with advanced disease and decreased overall survival in ovarian cancer patients

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Conclusion