Tumor-derived Lactate Induces M2 Macrophage Polarization Via the Activation of the ERK/STAT3 Signaling Pathway in Breast Cancer

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2018 Feb 23

PMID 29468929

Citations 202

Authors

Xianmin Mu

Wei Shi

Yue Xu

Che Xu

Ting Zhao

Biao Geng

Jing Yang

Jinshun Pan

Shi Hu

Chen Zhang

Juan Zhang

Chao Wang

Jiajia Shen

Yin Che

Zheng Liu

Yuanfang Lv

Hao Wen

Qiang You

Affiliations

Soon will be listed here.

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.

Citing Articles

The role of mA modification during macrophage metabolic reprogramming in human diseases and animal models.

Wang H, Xu P, Yin K, Wang S Front Immunol. 2025; 16:1521196.

PMID: 40066451 PMC: 11891544. DOI: 10.3389/fimmu.2025.1521196.

PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma.

Ding C, Yan F, Xu B, Qian H, Hong X, Liu S Cell Death Dis. 2025; 16(1):158.

PMID: 40050608 PMC: 11885674. DOI: 10.1038/s41419-025-07482-7.

Tumor-infiltrating myeloid cells; mechanisms, functional significance, and targeting in cancer therapy.

Toghraie F, Bayat M, Hosseini M, Ramezani A Cell Oncol (Dordr). 2025; .

PMID: 39998754 DOI: 10.1007/s13402-025-01051-y.

Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells.

Sangsuwan R, Thuamsang B, Pacifici N, Tachachartvanich P, Murphy D, Ram A Heliyon. 2025; 11(3):e42098.

PMID: 39975831 PMC: 11835580. DOI: 10.1016/j.heliyon.2025.e42098.

Lactate and lactylation in cancer.

Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y Signal Transduct Target Ther. 2025; 10(1):38.

PMID: 39934144 PMC: 11814237. DOI: 10.1038/s41392-024-02082-x.

References

Li R, Hebert J, Lee T, Xing H, Boussommier-Calleja A, Hynes R . Macrophage-Secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways. Cancer Res. 2016; 77(2):279-290. PMC: 5243269. DOI: 10.1158/0008-5472.CAN-16-0442. View

Zhao T, Mu X, You Q . Succinate: An initiator in tumorigenesis and progression. Oncotarget. 2017; 8(32):53819-53828. PMC: 5581152. DOI: 10.18632/oncotarget.17734. View

Colegio O, Chu N, Szabo A, Chu T, Rhebergen A, Jairam V . Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513(7519):559-63. PMC: 4301845. DOI: 10.1038/nature13490. View

Mondal S, Bhattacharya K, Mallick A, Sangwan R, Mandal C . Bak compensated for Bax in p53-null cells to release cytochrome c for the initiation of mitochondrial signaling during Withanolide D-induced apoptosis. PLoS One. 2012; 7(3):e34277. PMC: 3315518. DOI: 10.1371/journal.pone.0034277. View

Romero-Garcia S, Moreno-Altamirano M, Prado-Garcia H, Sanchez-Garcia F . Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance. Front Immunol. 2016; 7:52. PMC: 4754406. DOI: 10.3389/fimmu.2016.00052. View

Witkiewicz A, Whitaker-Menezes D, Dasgupta A, Philp N, Lin Z, Gandara R . Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 2012; 11(6):1108-17. PMC: 3335917. DOI: 10.4161/cc.11.6.19530. View

Mu X, Shi W, Sun L, Li H, Jiang Z, Zhang L . Pristimerin, a triterpenoid, inhibits tumor angiogenesis by targeting VEGFR2 activation. Molecules. 2012; 17(6):6854-68. PMC: 6268918. DOI: 10.3390/molecules17066854. View

Hart P, Mao M, de Abreu A, Ansenberger-Fricano K, Ekoue D, Ganini D . MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat Commun. 2015; 6:6053. PMC: 4319569. DOI: 10.1038/ncomms7053. View

Climaco-Arvizu S, Dominguez-Acosta O, Cabanas-Cortes M, Rodriguez-Sosa M, Gonzalez F, Vega L . Aryl hydrocarbon receptor influences nitric oxide and arginine production and alters M1/M2 macrophage polarization. Life Sci. 2016; 155:76-84. PMC: 6300993. DOI: 10.1016/j.lfs.2016.05.001. View

10.

Issa M, Wijeratne E, Gunatilaka A, Cuendet M . Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells. Front Pharmacol. 2017; 8:610. PMC: 5596074. DOI: 10.3389/fphar.2017.00610. View

11.

Holm E, Hagmuller E, Staedt U, Schlickeiser G, Gunther H, Leweling H . Substrate balances across colonic carcinomas in humans. Cancer Res. 1995; 55(6):1373-8. View

12.

Ding C, Guo Y, Li H, Wang J, Zeng X . Red nucleus interleukin-6 participates in the maintenance of neuropathic pain through JAK/STAT3 and ERK signaling pathways. Exp Neurol. 2017; 300:212-221. DOI: 10.1016/j.expneurol.2017.11.012. View

13.

Niu Z, Shi Q, Zhang W, Shu Y, Yang N, Chen B . Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nat Commun. 2017; 8(1):766. PMC: 5626701. DOI: 10.1038/s41467-017-00523-6. View

14.

Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B . Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene. 2017; 36(42):5829-5839. DOI: 10.1038/onc.2017.188. View

15.

Chen X, Yu T, Zhang J, Li Y, Chen H, Yang G . CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis. Oncogene. 2017; 36(35):5045-5057. PMC: 5582214. DOI: 10.1038/onc.2017.118. View

16.

Zhang W, Xu W, Xiong S . Macrophage differentiation and polarization via phosphatidylinositol 3-kinase/Akt-ERK signaling pathway conferred by serum amyloid P component. J Immunol. 2011; 187(4):1764-77. DOI: 10.4049/jimmunol.1002315. View

17.

Raggi F, Pelassa S, Pierobon D, Penco F, Gattorno M, Novelli F . Regulation of Human Macrophage M1-M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1. Front Immunol. 2017; 8:1097. PMC: 5594076. DOI: 10.3389/fimmu.2017.01097. View

18.

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

19.

Batista P, de Lima K, Pinto F, Tavares J, de A Uchoa D, Costa-Lotufo L . Withanolides from leaves of cultivated Acnistus arborescens. Phytochemistry. 2016; 130:321-7. DOI: 10.1016/j.phytochem.2016.07.003. View

20.

Zhou J, Zhao T, Ma L, Liang M, Guo Y, Zhao L . Cucurbitacin B and SCH772984 exhibit synergistic anti-pancreatic cancer activities by suppressing EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling. Oncotarget. 2017; 8(61):103167-103181. PMC: 5732720. DOI: 10.18632/oncotarget.21704. View