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

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

Author information

1
a Department of Biotherapy , Second Affiliated Hospital, Nanjing Medical University , Nanjing, Jiangsu 210011 , China.
2
b Department of Drug Screening and Evaluation , Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu 210023 , China.
3
c Department of Drug Clinical Trial Institution , Second Affiliated Hospital, Nanjing Medical University , Nanjing, Jiangsu 210011 , China.
4
d Department of Surgery , Second Affiliated Hospital, Nanjing Medical University , Nanjing, Jiangsu 210011 , China.
5
e Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University , Nanjing, Jiangsu 210011 , China.
6
f Department of Immunology , Nanjing Medical University , Nanjing, Jiangsu 211166 , China.
7
g Key Laboratory for Aging & Disease, Nanjing Medical University , Nanjing , Jiangsu, China.

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

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