Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-β1–IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer

SIMPLE SUMMARY: This study clarified that in the tumor microenvironment, tumor cell-derived TGF-β1 induces the appearance of an IGFBP7(+) CAFs subgroup, and its higher IGFBP7 extracellular secretion level accelerated the progression of tumors. Our work suggests that IGFBP7 is a novel predictive marker for clinical outcomes in gastric cancer patients. ABSTRACT: Patients with infiltrative-type gastric cancer (GC) (Ming’s classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is still unclear. Based on our proteomics data, TCGA data analysis, and immunohistochemical staining results, significantly higher expression of IGFBP7 was observed in GC, especially in the infiltrative type, and was associated with a poor prognosis. Combining single-cell transcriptome data from GEO and multiple immunofluorescence staining on tissue showed that the differential expression of IGFBP7 mainly originated from myofibroblastic CAFs, the subgroup with higher expression of PDGFRB and α-SMA. After treating primary normal fibroblasts (NFs) with conditional medium or recombined protein, it was demonstrated that XGC-1-derived TGF-β1 upregulated the expression of IGFBP7 in the cells and its secretion via the P-Smad2/3 pathway and mediated its activation with higher FAP, PDGFRB, and α-SMA expression. Then, either conditional medium from CAFs with IGFBP7 overexpression or recombined IGFBP7 protein promoted the migration, invasion, colony formation, and sphere growth ability of XGC-1 and MGC-803, respectively. Moreover, IGFBP7 induced EMT in XGC-1. Therefore, our study clarified that in the tumor microenvironment, tumor-cell-derived TGF-β1 induces the appearance of the IGFBP7(+) CAF subgroup, and its higher IGFBP7 extracellular secretion level accelerates the progression of tumors.