The apelin-apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116(sh p53) cells) was significantly lower than in control colon cancer cells (HCT116(sh control) cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116(sh p53) cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.