Bone Marrow-Derived Mesenchymal Stem Cells Regulate Epithelial-Mesenchymal Transitions and Gastric Cancer Stem Cells

Keishiro Aoyagi, Junya Kizaki, Taro Isobe, Taizan Minami, Yoshito Akagi

Abstract


Tumorigenesis is driven by alterations in tumor cells and also changes in the stromal microenvironment. Mesenchymal stem cells (MSCs) are promising candidates for the treatment of various tumors. MSCs are unlikely to be rejected by the immune system, could potentially home to the tumor site, and may interact with tumor cells to influence their growth and metastasis. Using mouse models of inflammation-induced gastric cancer, at least 20% of cancer-associated fibroblasts were found to originate from bone marrow (BM) and were derived from MSCs. Direct contact between BM-derived MSCs (BM-MSCs) and gastric cancer cells in vitro increases the proportion of CD133-positive gastric cancer cells. This mechanism is thought to involve stimulation of Wnt-5a and transforming growth factor (TGF)-β by BM-BMCs, directly affecting the gastric cancer cells. Moreover, direct contact between BM-MSCs and gastric cancer cells increases the expression of vimentin and Snail, which is a transcription factor that mediates epithelial-mesenchymal transitions (EMT). Human BM-MSCs can enhance the proliferation, invasion, and chemoresistance of gastric cancer cells. The regulatory mechanism involved is likely associated with increased expression of stem cell markers and EMT-related factors in gastric cancer cells. CD271, which is a marker of BM-MSCs, is expressed in scirrhous carcinoma, and the expression of Wnt-5a and TGF-β in cancer cells is up-regulated.BM-MSCs provide an advantageous tumor microenvironment for gastric cancer. Moreover, BM-MSC-related molecules may be considered biomarkers of gastric cancer.


Keywords


Bone Marrow;Mesenchymal Stem Cells; Epithelial-Mesenchymal Transition; Gastric Cancer; Cancer Stem Cells

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