GRP78 secreted by tumor cells stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts

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• 作者：Yanan Peng ; Zongwei Li ; Zhuoyu Li
• 关键词：CAFs ; cancer-associated fibroblasts ; MSCs ; mesenchymal stem cells ; ER ; endoplasmic reticulum ; 伪-SMA ; 伪-smooth muscle actin ; HBMSCs ; human bone marrow mesenchymal stem cells ; BMMSCs ; murine bone marrow mesenchymal stem cells ; SDF-1 ; stromal cell-derived factor 1 ; GRP78 ; glucose-regulated protein 78 ; BiP ; immunoglobulin heavy chain binding protein ; FBS ; fetal bovine serum ; IPTG ; isopropyl-尾-d-thiogalactoside ; PBS ; phosphate-buffered saline ; ECL kit ; enhanced chemiluminescence kit ; HRP-tagged se
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：1 November, 2013
• 年：2013
• 卷：440
• 期：4
• 页码：558-563
• 全文大小：831 K

文摘

Cancer-associated fibroblasts (CAFs), one type of tumor-associated stromal cells, have been shown to provide a favorable environment for the malignant tumor progression. Extensive reports have demonstrated that mesenchymal stem cells (MSCs) can function as precursors for CAFs. However, the mechanisms by which tumor cells induce the transition of MSCs to CAFs have not been well established. GRP78, traditionally known as an endoplasmic reticulum (ER) chaperone, has been identified to overexpress in a variety of tumor entities and be involved in promoting survival and chemoresistance of tumor cells. Here, we interrogated the role of GRP78 in the generation of CAFs from MSCs. The results showed that GRP78 treatment induced expression of 伪-smooth muscle actin (伪-SMA), a marker for CAFs, in human bone marrow mesenchymal stem cells (HBMSCs) as well as murine bone marrow mesenchymal stem cells (BMMSCs). This phenomenon was correlated with the stimulated phosphorylation of Smad2/3. Furthermore, the GRP78-induced 伪-SMA expression in HBMSCs was obviously attenuated by SB431542, a TGF-尾 type I receptor kinase inhibitor. Taken together, the present data suggested that tumor-derived secreted GRP78 elicited the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to CAFs through activating TGF-尾/Smad signaling pathway, which may represent a novel mechanism for transition of BMSCs to CAFs and a hitherto unknown function of GRP78 in the tumor microenvironment.