Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer |
| |
Authors: | Xianmin Mu Wei Shi Yue Xu Che Xu Ting Zhao Biao Geng |
| |
Institution: | 1. Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China;2. Department of Drug Screening and Evaluation, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu 210023, 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 breast cancer angiogenesis STAT3-ERK1/2 signaling |
|
|