Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line.
Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line.
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DOI：
10.1186/1471-2407-12-139
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发表时间：
2012-04-04
期刊：
影响因子：
3.8
通讯作者：
Gomes CM
中科院分区：
文献类型：
--
作者：
Martins-Neves SR;Lopes ÁO;do Carmo A;Paiva AA;Simões PC;Abrunhosa AJ;Gomes CM
骨肉瘤是一种间质来源的成骨肿瘤，其临床表现与癌症干细胞模型一致。具有干细胞样特性的细胞（CSC）已在几种肿瘤中被鉴定，并被假设为对治疗的相对抗性和肿瘤复发的原因。在这项研究中，我们的目的是确定和表征在人类骨肉瘤细胞系中的CSCs群体，并探讨其在传统治疗反应中的作用。使用球体形成测定从人MNNG/HOS细胞系分离CSC，并在自我更新、间充质干细胞特性、多能性标记物和ABC转运蛋白的表达、代谢活性和致瘤性方面进行表征。分析了细胞对常规化疗药物和辐射的敏感性，并将其与细胞周期诱导的改变和凋亡相关。发现分离的CSC具有自我更新和多潜能分化能力，表达多能胚胎干细胞Oct 4和Nanog的标志物以及ABC转运蛋白P-糖蛋白和BCRP，表现出低代谢活性并在无胸腺小鼠中诱导肿瘤。与亲本MNNG/HOS细胞相比，CSCs对化疗和放疗的抵抗力相对更强。没有一种治疗在CSC中诱导显著的细胞周期改变和凋亡。MNNG/HOS骨肉瘤细胞含有干细胞样细胞群，对常规化疗剂和放射相对耐受。这种耐药表型似乎与某些干细胞特征有关，即药物外排转运蛋白P-糖蛋白和BCRP的高表达及其静止性质，这可能为骨肉瘤中常见的治疗耐药和复发提供生物学基础。
Osteosarcoma is a bone-forming tumor of mesenchymal origin that presents a clinical pattern that is consistent with the cancer stem cell model. Cells with stem-like properties (CSCs) have been identified in several tumors and hypothesized as the responsible for the relative resistance to therapy and tumor relapses. In this study, we aimed to identify and characterize CSCs populations in a human osteosarcoma cell line and to explore their role in the responsiveness to conventional therapies. CSCs were isolated from the human MNNG/HOS cell line using the sphere formation assay and characterized in terms of self-renewal, mesenchymal stem cell properties, expression of pluripotency markers and ABC transporters, metabolic activity and tumorigenicity. Cell's sensitivity to conventional chemotherapeutic agents and to irradiation was analyzed and related with cell cycle-induced alterations and apoptosis. The isolated CSCs were found to possess self-renewal and multipotential differentiation capabilities, express markers of pluripotent embryonic stem cells Oct4 and Nanog and the ABC transporters P-glycoprotein and BCRP, exhibit low metabolic activity and induce tumors in athymic mice. Compared with parental MNNG/HOS cells, CSCs were relatively more resistant to both chemotherapy and irradiation. None of the treatments have induced significant cell-cycle alterations and apoptosis in CSCs. MNNG/HOS osteosarcoma cells contain a stem-like cell population relatively resistant to conventional chemotherapeutic agents and irradiation. This resistant phenotype appears to be related with some stem features, namely the high expression of the drug efflux transporters P-glycoprotein and BCRP and their quiescent nature, which may provide a biological basis for resistance to therapy and recurrence commonly observed in osteosarcoma.
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