放化疗诱导肿瘤相关成纤维细胞分泌TNFSF4促进肺腺癌顺铂耐药的机制研究

The impact of cancer-associated fibroblasts (CAFs) on cancer cells remains unclear. Some studies revealed CAFs may relate with drug resistance. By means of mimicking CAFs with human lung fibroblasts, indirect co-culture in vitro, gene expression screening, and histological evaluation, our preliminary study discovered CAFs after exposure to radiotherapy or chemotherapy may secrete tumor necrosis factor superfamily member 4 (TNFSF4) to promote cisplatin resistance in lung adenocarcinoma. Some reports showed TNFSF4, interacting with its receptor TNFRSF4, could activate NF-κB/Bcl-xl signaling pathway to inhibit apoptosis independently or through cross-talking with PI-3K/Akt pathway. Thus we hypothesized that it may be the molecular mechanism of cisplatin resistance promoted by TNFSF4 secreted from CAFs after radiotherapy or chemotherapy in lung adenocarinoma. We intended to validate our hypothesis in vitro and in vivo by molecular and cellular biological technologies. The work would reveal new mechanisms of therapeutic resistance of lung adenocarcinoma from the angle of tumor microenvironment and help explore a potential novel target for inhibiting lung adenocarcinoma chemoresistance.

肿瘤相关成纤维细胞（CAFs），特别是经临床治疗后的CAFs，对肿瘤细胞的影响至今仍不明确，有报道提示可能与肿瘤耐药有关。本课题组前期应用人肺成纤维细胞模拟肺腺癌CAFs，并通过体外间接共培养模型、芯片筛选及组织学验证等手段发现在放疗或化疗后CAFs可能通过旁分泌肿瘤坏死因子超家族成员4（TNFSF4）促进肺腺癌细胞对顺铂耐药。有报道提示TNFSF4作用于其受体TNFRSF4后可独立或与PI-3K/Akt信号通路crosstalk激活下游NF-κB/Bcl-xl信号通路，抑制细胞凋亡。故推测这可能是放疗或化疗后CAFs分泌TNFSF4介导肺腺癌细胞顺铂耐药的分子机制。本课题拟在前期工作基础上，通过分子及细胞生物学手段研究放疗或化疗后CAFs通过旁分泌TNFSF4介导肺腺癌顺铂耐药的作用及其分子机制。本项目将从肿瘤微环境角度揭示肺腺癌新的耐药机制，同时也可能为临床抑制肺腺癌耐药提供新的靶点。

肿瘤微环境中肿瘤相关成纤维细胞在肿瘤化疗耐药中起关键性作用。本项目研究结果提示肿瘤相关成纤维细胞在应激条件下（缺氧、放疗或化疗）能够通过旁分泌肿瘤坏死因子超家族成员4（TNFSF4）促进肺腺癌细胞对顺铂耐药。进一步研究结果提示TNFSF4通过作用于其受体TNFRSF4后可激活PI-3K/Akt信号通路和NF-κB/Bcl-xl信号通路，抑制细胞凋亡。本项目通过分子及细胞生物学手段研究应激状态下肿瘤相关成纤维细胞通过旁分泌TNFSF4介导肺腺癌顺铂耐药的作用及其分子机制，将为临床抑制肺腺癌耐药提供新的靶点。