Lactate-activated macrophages induced aerobic glycolysis and epithelial-mesenchymal transition in breast cancer by regulation of CCL5-CCR5 axis: a positive metabolic feedback loop.

Sensen Lin,Hongyang Li,Xiaodan Lyu,Shengtao Yuan,Jun Yu,Luyong Zhang,Danyu Du,Li Sun,Nan Su,Xiongfei Ai

doi:10.18632/oncotarget.22786

Sensen Lin, Hongyang Li + Show 8 more

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https://doi.org/10.18632/oncotarget.22786

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Abstract

Aberrant energy metabolism is critical for cancer progression. Tumor-associated macrophages (TAMs) can stimulate tumor angiogenesis and enhance cancer metastasis; however, the metabolic interaction between cancer cells and macrophages characterized by lactate shuttles remains unclear. Here, we showed that lactate activated human macrophages to a TAM-like phenotype and stimulated the secretion of CCL5 by activation of Notch signaling in macrophages. Reciprocally, CCL5 increased cell migration, induced cancer cell EMT, and promoted aerobic glycolysis in breast cancer cells, suggesting a positive metabolic feedback loop in the co-culture system. Inhibition of CCR5, the cognate receptor of CCL5, or neutralization of CCL5, broke the metabolic loop and decreased cancer cell migration and EMT. Inhibition of aerobic glycolysis significantly reduced breast cancer cell EMT, indicated that aerobic glycolysis was necessary for the invasive phenotype of cancer cells. We further showed that TGF-β signaling regulated the expression of CCR5 in the co-culture system, and CCL5 induced glycolysis by mediation of AMPK signaling. The expression of CCL5-CCR5 axis was highly associated with macrophage infiltration, TGF-β and p-AMPK in clinical samples. CCL5-CCR5 axis promoted breast cancer metastasis in vivo. Our findings suggested a pivotal role of CCL5-CCR5 axis in the metabolic communication between cancer cells and macrophages.

Highlights

Aberrant energy metabolism is a hallmark of cancer
As cancer usually prefers to aerobic glycolysis and produces high levels of lactic acid, these results suggested a possible correlation of lactate, Tumorassociated macrophages (TAMs) and CC chemokine ligand 5 (CCL5) in breast cancer
We found that cancer cell derived-lactate increased the secretion of CCL5 through Notch signaling in tumor-associated macrophages, and CCL5 in turn induced epithelial-mesenchymal transition (EMT) and aerobic glycolysis in breast cancer cells (Figure 9)

Summary

Introduction

Even in the presence of ample oxygen, cancer cells source their energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, which is known as aerobic glycolysis or the Warburg effect [1]. Aerobic glycolysis helps to create a low pH microenvironment that may confer a proliferation advantage for cancer cells. An end product of aerobic glycolysis, is secreted into tumor microenvironment to fuel other cancer cells that do not have enough energy supplies [4]. Www.impactjournals.com/oncotarget lactate produced by cancer-associated fibroblasts can be utilized as energy fuel for oxygenated tumor cells [5, 6]. Understanding the metabolic communication in tumor microenvironment characterized by lactate shuttles is critical to elucidate the heterogeneous biological features of tumor

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