CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis

Darrin Gao,Lisa H Cazares,Eleanor N Fish

doi:10.1186/s12885-017-3817-0

Abstract

BackgroundIn earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.MethodsUsing the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus – polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.ResultsWe provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5−/− cells, that exhibit reduced glycolytic metabolism.ConclusionsThese findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.

Highlights

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism
We showed that CCL5 engagement with its cognate receptor, CCR5, results in the upregulation of mRNA translation of pro-survival factors leading to enhanced proliferation in MCF-7 breast cancer cells [20]
We provide evidence that in the absence of CCR5, the early events associated with rapid tumor growth are diminished; our studies identify a direct correlation between reduced tumor proliferation and decreased metabolic activity

Summary

Introduction

In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism. Metabolic reprogramming is critical for tumor development [1]. During conditions of either nutrient sufficiency or deficiency, tumors will reprogram their metabolic activity towards anabolic or catabolic metabolism, respectively [2,3,4]. The Warburg effect of aerobic glycolysis associated with glucose uptake and increases in glycolytic flux enables tumor cells to invoke. CCL5 levels are markedly higher in more aggressive forms of breast cancer and are predictive of rapid disease progression in stage II breast cancer patients [15].

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