Platelets enhance the ability of bone-marrow mesenchymal stem cells to promote cancer metastasis.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been identified to be closely associated with cancer progression. Our previous experimental results showed that BM-MSCs promote tumor growth and metastasis of gastric cancer through paracrine-soluble cytokines or exosomes. However, the elements that affect the role of BM-MSCs in promoting tumor metastasis are not clear. It is known that thrombocytosis in cancer patients is very common. Recently, platelets are recognized to play a critical role in tumor progression. PURPOSE: This study aims to observe the effect of BM-MSCs which were co-cultured with platelets on tumor cell metastasis. METHODS: Platelet aggregation rate and the expression of P-selectin of platelets co-incubated with conditioned medium of SGC-7901 cells and BM-MSCs were detected by flow cytometry and platelet aggregometer. We also analyzed the change of BM-MSCs after co-incubation with platelets or platelets which were treated with SGC-7901 cells using transwell assay and Western blot analysis. The proliferation and migration ability and expression of VEGF, c-Myc, and sall-4 in SGC-7901 cells treated with medium of BM-MSCs which were co-cultured with platelets were detected. SGC-7901 cells were injected into Balb/c nude mice and the extent of lung metastasis was observed. Both in vitro and in vivo assays were used to analyze the effect of platelets on enhancing the ability of BM-MSCs to promote cancer metastasis. RESULTS: Results suggested that BM-MSCs and tumor cells can promote platelet aggregation rate and the expression of P-selectin. The protein levels of α-smooth muscle actin, vimentin, and fibroblast activation protein in BM-MSCs were higher after co-incubation with platelets, and SB431542 was used to confirm the effect of TGF-ß on transdifferentiation of BM-MSCs into cancer-associated fibroblasts. Medium of BM-MSCs treated with platelets enhanced the proliferation and migration ability of SGC-7901 cells. More lung metastases were found in mice which were injected with SGC-7901 cells treated with conditioned medium from BM-MSCs co-incubated with platelets. CONCLUSION: Tumor cells and BM-MSCs activate platelets which can change the characteristics of BM-MSCs through secretion of TGF-ß. Moreover, we found that platelets enhanced the effect of BM-MSCs on tumor metastasis, which suggested a potential target and approach for gastric cancer therapy.

Human Gastric Cancer Mesenchymal Stem Cell-Derived IL15 Contributes to Tumor Cell Epithelial-Mesenchymal Transition via Upregulation Tregs Ratio and PD-1 Expression in CD4+T Cell.

Several studies show that mesenchymal stem cells (MSCs) homing to tumors not only provide the microenvironment for tumor cells but also promote tumor growth and metastasis. However, the exact mechanism remains unclear. Our study aims to investigate the role of gastric cancer MSCs (GCMSCs)-derived IL15 during GC progression. The effects of IL15 secreted by GCMSCs on GC development were evaluated by detecting the stemness, epithelial-mesenchymal transition (EMT), and migration abilities of GC cell lines. The expression of IL15 in serum and tissues of GC patients was also assessed. We found that IL15 derived from GCMSCs enhanced stemness, induced EMT and promoted migration of GC cell lines. The level of IL15 was higher in GC patients both in serum and tissues compared with that in healthy donors, which was associated with lymph node metastasis. In addition, the results have shown that IL15 in GC microenvironment was mainly produced by GCMSCs. Moreover, IL15 upregulated Tregs ratio through activation of STAT5 in CD4+T cells was accompanied by elevated expression of programmed cell death protein-1 (PD-1). Our data proved that the high concentration of IL15 in tumor microenvironment, which was mainly secreted by GCMSCs, may contribute to tumor cell metastasis and offer a new opportunity to develop effective therapeutics for intercepting tumor progression.

Exosomes derived from human umbilical cord mesenchymal stem cells improve myocardial repair via upregulation of Smad7.

It has been previously reported that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC)­exosomes exhibit cardioprotective effects on the rat acute myocardial infarction (AMI) models and cardiomyocyte hypoxia injury models in vitro, however the exact mechanisms involved require further investigation. The present study aimed to investigate the repair effects of hucMSC­exosomes on myocardial injury via the regulation of mothers against decapentaplegic homolog 7 (Smad7) expression. Compared with sham or normoxia groups (in vivo and in vitro, respectively), western blotting demonstrated that Smad7 expression was significantly decreased in the borderline area of infraction myocardium and in H9C2(2­1) cells following hypoxia­induced injury. Additionally, microRNA (miR)­125b­5p expression was markedly increased using reverse transcription­quantitative polymerase chain reaction, but was reversed by hucMSC­exosomes. Trypan blue staining and lactate dehydrogenase release detection demonstrated that cell injury was significantly increased in the AMI + PBS and hypoxia group compared with in the sham and normoxia groups and was inhibited by hucMSC­exosomes. A dual luciferase reporter gene assay confirmed that Smad7 is a target gene of miR­125b­5p. In addition, miR­125b­5p mimics promoted H9C2(2­1) cell injury following 48 h exposure to hypoxia. Downregulation of Smad7 expression under hypoxia was increased by miR­125b­5p mimics compared with the mimic negative control, and hucMSC­exosomes partially alleviated this phenomenon. In conclusion, hucMSC­exosomes may promote Smad7 expression by inhibiting miR­125b­5p to increase myocardial repair. The present study may provide a potential therapeutic approach to improve myocardial repair following AMI.