a Department of Biotherapy , Second Affiliated Hospital, Nanjing Medical University , Nanjing, Jiangsu 210011 , China.
b Department of Drug Screening and Evaluation , Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu 210023 , China.
Cell Cycle. 2018;17(4):428-438. doi: 10.1080/15384101.2018.1444305. Epub 2018 Mar 27.
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.
肿瘤相关巨噬细胞（TAM）是肿瘤微环境（TME）的主要组成部分，能够促进癌症进展。然而，M2 样 TAM 形成的机制仍不清楚。在这里，我们表明乳酸是 TME 中的关键致癌代谢物，可驱动巨噬细胞 M2 极化，促进乳腺癌增殖、迁移和血管生成。此外，我们发现 ERK/STAT3 的激活是乳酸信号通路中的主要信号分子，加深了我们对乳酸如何教育 TAM 的分子理解。此外，通过消除乳酸诱导的 M2 巨噬细胞极化，抑制 ERK/STAT3 信号可减少肿瘤生长和血管生成。最后，天然化合物 withanolide D 的研究数据为 ERK/STAT3 信号作为预防和治疗乳腺癌的潜在治疗策略提供了证据。这些发现表明，通过刺激巨噬细胞 M2 样极化，乳酸-ERK/STAT3 信号通路是乳腺癌进展的驱动因素，并揭示了乳腺癌治疗的潜在新治疗靶点。
