Estrogen-responsive cancer-associated fibroblasts promote invasive property of gastric cancer in a paracrine manner via CD147 production

Abstract

Estrogen signaling has been extensively studied, especially in cancers that express estrogen receptor alpha (ERalpha). However, little is known regarding the effect of estrogen on cancer-associated fibroblasts (CAFs). Here, we explored the role of estrogen signaling of CAFs in gastric cancer (GC) progression. We investigated the phenotypic changes in CAFs upon 17beta-estradiol (E2) treatment using ERalpha-negative/positive CAFs, and the conditioned media (CM) collected from these were compared with regard to cancer cell proliferation, migration, and invasion. A paracrine factor was found using a cytokine array and was confirmed using qRT-PCR, western blotting, and enzyme-linked immunosorbent assays. ERalpha-CD147-matrix metalloproteinase (MMP) axis was confirmed by knockdown experiments using specific siRNAs. We found that a subset of CAFs expressed ERalpha. ERalpha-positive CAFs were responsive to E2, inducing ERalpha expression in a dose-dependent manner. Although E2 did not induce the proliferation of ERalpha-positive CAFs, the CM from E2-bound ERalpha-positive CAFs significantly promoted cancer cell migration and invasion. Cytokine array revealed that CD147 was induced in ERalpha-positive CAFs upon E2 treatment; this was mediated via ERalpha. Increased CD147 upregulated MMP2 and MMP9 in CAFs, and also influenced cancer cells in a paracrine manner to increase MMPs and CD147 in cancer cells. High CD147 expression in tumor tissue was associated with a worse prognosis in GC patients. Our data suggest that estrogen signaling activation in CAFs and the byproduct CD147 are among the critical mediators between the interplay of CAFs and cancer cells to facilitate cancer progression.