Ji Nuo, Yu Ji-Wei, Ni Xiao-Chun, Wu Ju-Gang, Wang Shou-Lian, Jiang Bo-Jian
Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Mohe Rd 280, Shanghai, 201900, People's Republic of China.
Tumour Biol. 2016 Nov;37(11):14637-14651. doi: 10.1007/s13277-016-5319-0. Epub 2016 Sep 12.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited to primary tumours to compose the tumour microenvironment. In various cancers, CD133-positive cells have been shown to possess cancer stem cell properties that confer chemoresistance. This study aimed to investigate the role of BM-MSCs in the anti-tumour drug resistance of CD133-expressing gastric cancer cells and explore the underlying mechanisms that governing this role. We found that CD133 gastric cancer cells displayed more resistance to chemotherapeutics than CD133 cells. In addition, BM-MSCs increased the anti-apoptotic abilities and chemoresistance of CD133 cells via upregulation of Bcl-2 and downregulation of BAX. Mechanistically, BM-MSCs triggered activation of the PI3K/Akt signalling cascade in CD133 cells. Blocking the PI3K/Akt pathway inhibited the promotion of chemoresistance. Furthermore, BM-MSCs enhanced the drug resistance of CD133-overexpressing cells in vitro and in vivo, but not that of CD133-knockdown cells, which demonstrated the contribution of CD133 to this process. In conclusion, we demonstrated that BM-MSCs increased the anti-apoptotic abilities and drug resistance of CD133-expressing cells via activation of the PI3K/Akt pathway following Bcl-2 upregulation and BAX downregulation, in which CD133 played a significant role. Targeting this route may help improve the efficacy of chemotherapy in gastric cancer.
骨髓来源的间充质干细胞（BM-MSCs）被募集到原发性肿瘤中以构成肿瘤微环境。在各种癌症中，已证明CD133阳性细胞具有赋予化疗抗性的癌症干细胞特性。本研究旨在探讨BM-MSCs在表达CD133的胃癌细胞的抗肿瘤耐药性中的作用，并探索调控这一作用的潜在机制。我们发现，与CD133阴性细胞相比，CD133阳性胃癌细胞对化疗药物表现出更强的抗性。此外，BM-MSCs通过上调Bcl-2和下调BAX增强了CD133阳性细胞的抗凋亡能力和化疗抗性。机制上，BM-MSCs触发了CD133阳性细胞中PI3K/Akt信号级联的激活。阻断PI3K/Akt途径可抑制化疗抗性的增强。此外，BM-MSCs在体外和体内均增强了过表达CD133细胞的耐药性，但对敲低CD133的细胞则无此作用，这证明了CD133在这一过程中的作用。总之，我们证明BM-MSCs通过上调Bcl-2和下调BAX后激活PI3K/Akt途径，增强了表达CD133细胞的抗凋亡能力和耐药性，其中CD133发挥了重要作用。靶向这一途径可能有助于提高胃癌化疗的疗效。
