期刊
CELL CYCLE
卷 17, 期 4, 页码 428-438出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2018.1444305
关键词
Lactate; M2 macrophage polarization; breast cancer; angiogenesis; STAT3-ERK1/2 signaling
类别
资金
- Jiangsu Provincial Natural Science Foundation [BK20141488]
- Jiangsu Province's Key Provincial Talents Program [QNRC2016680]
- Projects of medical and health technology development program in Nanjing city [201715014]
- Jiangsu Provincial Innovation Team Program Foundation [2015ToQY]
- Jiangsu Provincial 333 high level talents Program Foundation [CRA2016525]
- Jiangsu Provincial Six talent Peaks Program Foundation [2015-WSW-010]
- Jiangsu Provincial Distinguished Medical Experts Program Foundation [2014ToQY]
- Preventive Medicine Foundation of Jiangsu Provincial Commission of Health and Family Planning [Y2013058]
- National Natural Science Foundation of China [81471543, 81402204, 81671543]
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.
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