Bone mesenchymal stem cells promote gastric cancer progression through TGF-β1/Smad2 positive feedback loop

Aims: Bone marrow-derived mesenchymal stem cells (BMSCs) have been proven to be recruited into the tumor microenvironment and contribute to gastric Cancer (GC) progression, but the underlying mechanism is still unclear. The purpose of this study is to explore the exact role and potential mechanism of BMSCs in the progression of GC.

Materials and methods: Bioinformatics analyzed were used to clarify the correlation between TGF-β1 and prognosis of gastric Cancer. Cell co-culture were used to explore the interaction between gastric Cancer cells (GCs) and BMSCs. Quantitative real time-PCR and Western blot assay were used to detect gene and protein expression, respectively. The biological characteristics of GCs and BMSCs were detected by immunofluorescence, Transwell migration, Elisa and invasion assay. Xenograft models in nude mice were constructed to evaluate GC development in vivo.

Key findings: TGF-β1 was overexpressed in GC cells and tissues, and is positively related to the poor prognosis of patients. TGF-β1 from GCs activated the SMAD2 pathway in BMSCs, promoting their differentiation into carcinoma-associated fibroblasts (CAFs) and TGF-β1 expression. Concomitantly, TGF-β1 secreted by CAFs activate SMAD2 signaling in GC cells, thus inducing their epithelial-mesenchymal transition (EMT) and TGF-β1 secretion. BMSCs can dramatically promote the proliferation, migration, and invasion of GCs while blocking TGF-β1/SMAD2 positive feedback loop can reverse these effects.

Significance: The TGF-β1/SMAD2 positive feedback loop between GCs and BMSCs, promotes the CAFs differentiation of BMSCs and the epithelial-mesenchymal transition of GCs, resulting in the progression of GC.

Bone marrow-derived mesenchymal stem cells (BMSCs); Cancer-associated fibroblasts (CAFs); Gastric cancer (GC); TGF-β1/Smad2 pathway.