2. Academic Validation
  3. Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells

Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells

  • Mol Immunol. 2025 Jul:183:93-103. doi: 10.1016/j.molimm.2025.05.002.
Feng Huang 1,  Xiaoli Cao 2,  Jingyu Mei 3,  Chen Wu 3,  Wei Zhu 3,  Li Sun 4,  Chun Dai 5,  Mei Wang 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; Department of Clinical Laboratory, Maternal and Child Health Care Hospital of Kunshan, Suzhou, Jiangsu Province, China; Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu Province, China.
  • 2 Department of Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China.
  • 3 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China.
  • 4 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu Province, China. Electronic address: 823820834@qq.com.
  • 5 Department of General Surgery, Yangzhong People's Hospital Affiliated to medical college of Yangzhou University, Yangzhong, Jiangsu Province, China. Electronic address: dt7931@sina.com.
  • 6 Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; Institute of Cerebrovascular Disease, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China. Electronic address: wangmei2012@ujs.edu.cn.
PMID: 40347782 DOI: 10.1016/j.molimm.2025.05.002
Abstract

Metabolic reprogramming, exemplified by the "Warburg effect," is a hallmark of human cancers, leading to lactate buildup in tumors. Bone marrow-derived mesenchymal stem cells (BM-MSCs), key contributors to cancer-associated fibroblasts (CAFs), integrate into gastric Cancer stroma through interactions with Cancer cells. However, the role of lactate in activating BM-MSCs in this context remains unclear. Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965. Gastric Cancer cells released more lactate under hypoxia than normoxia. While normoxic gastric Cancer cells could educate BM-MSCs, hypoxic cells were more effective. However, the effects of the supernatant from gastric Cancer cells in both conditions were significantly reduced by AZD3965. Similarly, prevention of lactate production by oxamic acid sodium significantly reduced the effects observed. Lactate-activated BM-MSCs showed NF-κB signaling activation, increased IL-8 secretion, and no change in TGF-β signaling. These activated BM-MSCs promoted gastric Cancer cell migration and invasion through IL-8 secretion and enhanced resistance to CD8 + T cell cytotoxicity by upregulating PD-L1. Collectively, gastric Cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric Cancer.

Keywords

Bone marrow-derived mesenchymal stem cells; Cancer-associated fibroblasts; Gastric cancer; Lactate; Tumor microenvironment.

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