TNFα信号通路在化疗后残存胃癌细胞加速增殖中的作用

The effect of chemotherapy on most of advanced cancers is not good enough, which may be partially due to the phenomenon of accelerating proliferation of residual cancer cells after chemotherapy. In the past few years, mechanisms related to accelerating proliferation have been mainly focsed on residual cancer cells themselves or classical factors of microenviroment, such as stromal cell. However, we believe that the apoptotic or necrotic cancer cells may be the biggest colony and thus most important part of post-chemotherapy microenviroment, which may affect the biological behavior of residual cancer cells. Based on this hypothesis, we found that necrotic or apoptotic gastric cancer cells after chemotherapy could promote the proliferation of residual cancer cells on in vitro and in vivo models. TNFα was found to be a key mediator of this process, which might promote the proliferation of residual cancer cells through ROS signal. It is not know yet how gastric cancer cells after chemotherapy can produce TNFα and which signal pathways in residual cancer cells mediate the function of TNFα. The value of elucidating the mechanism of accelerating proliferation on potentially useful methods for diagnosis and therapy of gastric cancer is also not known. In the present study, we plan to further investigate the signal pathways that mediate the produce of TNFα after chemotherapy.We also plan to investigate the mechanisms of accelerating proliferation of residual cancer cells mediated by TNFα signal pathways in ROS-dependent and -independent manners.This study may help to uncover the mechanisms of accelerating proliferation of residual gastric cancer cells after chemotherapy. It may also present new evidences and basis for improving the effect of chemotherapy and reducing recurrence of gastric cancer.

大多晚期肿瘤的化疗效果并不理想，这与化疗后的残存癌细胞加速增殖密切相关。既往对残癌加速增殖的研究主要聚焦在残癌细胞本身或传统的基质细胞等微环境因素。我们认为，化疗后最大的微环境改变来自于大量凋亡坏死的癌细胞，它们可能对残存癌细胞的生物学行为产生重要影响。据此，我们首次在体内外模型上证实了化疗后凋亡坏死的胃癌细胞可促进残存癌细胞的加速增殖，揭示了TNFα是这一过程的关键介导分子，它可能通过ROS途径发挥促残癌增殖的作用。然而，化疗诱导胃癌细胞释放TNFα的机制和TNFα促进残癌加速增殖的具体途径尚不清楚，残癌加速增殖现象及机制的临床潜在诊治价值还有待明确。本课题拟在前期工作的基础上，进一步明确化疗后胃癌细胞上调TNFα的信号途径，探讨ROS依赖和非依赖的TNFα信号通路在残存胃癌加速增殖中的具体作用。研究结果有望首次揭示化疗后残存胃癌加速增殖的机理，为提高胃癌化疗效果、减少复发提供新依据。

化疗后胃癌细胞的加速再增殖是化疗抵抗和失败的重要原因，其机制尚不清楚。我们的为期一年的研究发现，TNFα是介导这一过程的关键分子。在体外混合培养和分离培养（Transwell小室）模型中均发现，化疗可诱导胃癌细胞释放TNFα，下调TNFα的表达可抑制残存胃癌细胞的增殖；体内裸鼠皮下混合种植模型的结果也提示，TNFα拮抗剂及腺病毒siRNA在体均可明显抑制化疗后的残存胃癌细胞的再增殖。混合培养模型的研究发现，化疗后残存的耐药细胞的HIF1、FoxM1、Cyclin D1等分子表达明显增加，下调或拮抗TNFα的表达可显著抑制上述分子的变化，推测ROS/HIF1/FoxM1通路可能介导了TNFα的促进残癌增殖作用。本研究为进一步揭示TNFα在化疗后残癌细胞加速再增殖中的机理奠定了良好的基础。