1. Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People's Republic of China.
2. Department of Thyroid and Breast Surgery, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430071, People's Republic of China.
3. Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China.
4. Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, 430071, People's Republic of China.
5. Department of Gastrointestinal Surgery, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People's Republic of China.
* Haitao Wu, Zhenxian Xiang, Guoquan Huang contributed equally to this work.
Peritoneal metastasis (PM) is most frequent in gastric cancer (GC) and cancer-associated fibroblasts (CAFs) play a critical role in this process. However, the concrete mechanism of crosstalk between CAFs and cancer cells in PM of GC remains unclear. Microarray sequencing of GC focus and PM lesions was performed, and biglycan (BGN) was screened for further study. Clinically, BGN expression was higher in GC tissues than adjacent normal tissues, and high expression correlated with poor prognosis. In vitro experiments demonstrated that BGN promoted tumor progression and the transformation of mesothelial cells (MCs) into cancer-associated fibroblasts like cells (CAFLCs). In turn, CAFLCs-derived fibroblast activation protein (FAP) facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells. GC-derived BGN combined with toll like receptor 2 (TLR2)/TLR4 on MCs to activate the NF-κB pathway and promote the transformation of MCs into CAFLCs by the recovery experiment, coimmunoprecipitation assay, nuclear and cytoplasmic protein extraction assay. CAFLCs-derived FAP could activate the JAK2/STAT3 signaling pathway in GC. Finally, activated STAT3 promoted BGN transcription in GC, resulting in a BGN/FAP-STAT3 positive feedback loop. Taken together, mutual interaction between tumor cells and activated MCs mediated by a BGN/FAP-STAT3 positive feedback loop facilitates PM of GC and provides a potential biomarker and therapeutic target for GC metastasis.
Keywords: biglycan, cancer-associated fibroblasts, fibroblast activation protein, gastric cancer, peritoneal metastasis