肿瘤相关成纤维细胞对宫颈癌预后及放疗抵抗的影响

Effect of Cancer-associated Fibroblasts on Prognosis and Radiotherapy Resistance in Cervical Cancer

目的探讨肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)与宫颈癌的预后和放疗抵抗之间的关系。方法收集76例宫颈癌活检组织及其临床病理学资料,检测组织中CAFs含量,并分析其与患者临床病理特征及预后的关系。从宫颈癌组织中提取并培养CAFs,通过与宫颈癌细胞株混合接种于裸鼠的体内成瘤实验和体外细胞共培养实验,观察CAFs对宫颈癌放疗敏感性的影响。检测接受放射处理后CAFs分泌肝细胞生长因子(HGF)水平的变化,共培养后宫颈癌细胞表面HGF受体c-Met的活性变化,探究CAFs参与放疗抵抗的可能机制。结果宫颈癌组织中的CAFs含量存在差异,CAFs高含量是宫颈癌复发的独立危险因素(HR=3.521,P<0.05)。体内实验结果显示,在放射治疗后,混合接种移植瘤组裸鼠比单纯肿瘤接种组能更快地从放疗导致的生长抑制中恢复(P<0.05)。体外实验结果显示,与对照组相比,CAFs与宫颈癌细胞共培养组的放疗抵抗性明显增加(P<0.05)。此外,经过照射后,CAFs分泌的HGF增加,共培养后宫颈癌细胞表面c-Met活性上调。结论在宫颈癌组织中,CAFs高含量与宫颈癌不良预后相关,其机制可能与CAFs通过HGF/c-Met通路介导宫颈癌的放疗抵抗有关。

Objective To investigate the relationship between cancer-associated fibroblasts(CAFs)and prognosis as well as radiotherapy resistance in cervical cancer.Methods In all,76cases of cervical cancer biopsy tissues and clinical pathological data were collected.The content of CAFs in the tissues was measured,and their relationship with clinical pathological features and prognosis was analyzed.CAFs were extracted and cultured from cervical cancer tissues.In vivotumorigenesis experiments were conducted by co-implanting CAFs with cervical cancer cells in nude mice.In vitro co-culture experiments were performed to observe the influence of CAFs on the radiotherapy sensitivity of cervical cancer.The changes in hepatocyte growth factor(HGF)secretion of CAFs after irradiation as well as changes in activity of HGF receptor c-Met on cervical cancer cell surface after CAFs co-culture were also examined.In this way,the possible mechanisms by which CAFs contribute to radiotherapy resistance were explored.Results The content of CAFs in cervical cancer tissues varied,and a high content of CAFs was an independent risk factor for cervical cancer recurrence(hazard ratio=3.521,P<0.05).In vivo experiments revealed that co-implanted tumor group recovered faster from the growth inhibition caused by radiotherapy compared to the group with sole tumor implantation(P<0.05).In vitro experiments revealed that co-culture group of CAFs and cervical cancer cells exhibited significantly increased resistance to radiotherapy compared to the control group(P<0.05).Furthermore,secretion of HGF by CAFs was increased after irradiation,and co-culture with CAFs upregulated the activity of c-Met on the surface of cervical cancer cells.Conclusion A high content of CAFs in cervical cancer tissues is associated with poor prognosis,possibly due to the involvement of CAFs in mediating radiotherapy resistance in cervical cancer through the HGF/c-Met pathway.