Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer

Cell Cycle. 2018;17(4):428-438. doi: 10.1080/15384101.2018.1444305. Epub 2018 Mar 27.

Abstract

Tumor-associated macrophages (TAM) are prominent components of tumor microenvironment (TME) and capable of promoting cancer progression. However, the mechanisms for the formation of M2-like TAMs remain enigmatic. Here, we show that lactate is a pivotal oncometabolite in the TME that drives macrophage M2-polarization to promote breast cancer proliferation, migration, and angiogenesis. In addition, we identified that the activation of ERK/STAT3, major signaling molecules in the lactate signaling pathway, deepens our molecular understanding of how lactate educates TAMs. Moreover, suppression of ERK/STAT3 signaling diminished tumor growth and angiogenesis by abolishing lactate-induced M2 macrophage polarization. Finally, research data of the natural compound withanolide D provide evidence for ERK/STAT3 signaling as a potential therapeutic strategy for the prevention and treatment of breast cancer. These findings suggest that the lactate-ERK/STAT3 signaling pathway is a driver of breast cancer progression by stimulating macrophage M2-like polarization and reveal potential new therapeutic targets for breast cancer treatment.

Keywords: Lactate; M2 macrophage polarization; STAT3-ERK1/2 signaling; angiogenesis; breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Humans
  • Lactic Acid / pharmacology*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphorylation / drug effects
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Tumor Microenvironment
  • Withanolides / pharmacology
  • Withanolides / therapeutic use

Substances

  • MRC1 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • STAT3 Transcription Factor
  • Withanolides
  • withanolide D
  • Lactic Acid
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding

This work was supported by the Jiangsu Provincial Natural Science Foundation [grant number BK20141488]; Jiangsu Province's Key Provincial Talents Program [grant number QNRC2016680]; Projects of medical and health technology development program in Nanjing city [grant number 201715014]; Jiangsu Provincial Innovation Team Program Foundation [grant number 2015ToQY]; Jiangsu Provincial 333 high level talents Program Foundation [grant number CRA2016525]; Jiangsu Provincial Six talent Peaks Program Foundation [grant number 2015-WSW-010]; Jiangsu Provincial Distinguished Medical Experts Program Foundation [grant number 2014ToQY]; Preventive Medicine Foundation of Jiangsu Provincial Commission of Health and Family Planning [grant number Y2013058]; National Natural Science Foundation of China [grant number 81471543], [grant number 81402204], [grant number 81671543]