Cross‐talk between gastric cancer and hepatic stellate cells promotes invadopodia formation during liver metastasis

• Published in: Cancer science 2024-02, Vol.115 (2), p.369-384
• Main Authors: Ren, Chuanfu, Yang, Zhi, Xu, En, Kang, Xing, Wang, Xingzhou, Sun, Qi, Wang, Chao, Zhang, Liang, Miao, Ji, Luo, Banxin, Chen, Kai, Liu, Song, Shen, Xiaofei, Lu, Xiaofeng, Yin, Kai, Wang, Meng, Xia, Xuefeng, Guan, Wenxian
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; c-Met protein; Cell adhesion & migration; Chemotherapy; Extracellular matrix; Gastric cancer; Growth factors; hepatic stellate cell; Hepatic Stellate Cells - metabolism; Hepatocyte growth factor; HGF/MET; Humans; invadopodia; Kinases; Ligands; Liver; Liver cancer; liver metastasis; Liver Neoplasms - pathology; Medical prognosis; Metastases; Metastasis; Original; Phosphatidylinositol 3-Kinases - metabolism; Platelet-derived growth factor; Platelet-derived growth factor receptors; Podosomes; Proteins; Proto-Oncogene Proteins c-sis - metabolism; Signal Transduction; Stellate cells; Stomach Neoplasms - pathology; Surgery; Survival analysis; Therapeutic targets; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.16023

In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia‐associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet‐derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto‐oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross‐talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRβ) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM. Invadopodia could serve as a biomarker of gastric cancer with liver metastasis. Cross‐talk between gastric cancer cells and hepatic stellate cells promotes invadopodia formation during liver metastasis through HGF/MET axes, which might represent potential therapeutic targets for gastric cancer with liver metastasis.