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首页> 外文期刊>International journal of hyperthermia: The official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group >Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation
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Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

机译：活化的肝星状细胞可促进余热后残留肝细胞癌从自噬生存发展为增殖

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Microscopic residual tumor often occurs after thermal ablation for medium-large hepatocellular carcinoma (HCC), leading to early aggressive recurrence or late relapse during follow-up. The mechanism how microscopic residual HCC cells survive sublethal heat stress and develop rapid outgrowth remains poorly understood. HCC cells were exposed to sublethal heat treatment and co-cultured with conditioned media from activated HSCs (HSC-CM). Changes of cell proliferation, parameters of cell autophagy and activation of signaling pathways in heat-treated residual HCC cells were analyzed. An HCC orthotopic model was subjected to partial thermal ablation and antitumor effects of a combined treatment regimen were studied. HCC cells survived sublethal heat stress via activation of autophagy. HSC-CM enhanced autophagic survival within 24?h and then promoted proliferation of heat-treated residual HCC cells through HGF/c-Met signaling. Inhibition of autophagy or c-Met increased apoptosis of heat-treated residual HCC cells and reversed the protective effect of HSC-CM. HGF modulated biological status in autophagic survival or proliferation of heat-treated residual HCC through HGF/c-Met/ERK signaling and downstream components of ATG5/Beclin1 or cyclinD1. In an animal model, inhibiting autophagy in combination with c-Met inhibitor significantly thwarted tumor progression of residual HCC after incomplete thermal ablation via the suppressed autophagy, the decreased proliferation and the increased apoptosis. Activated HSCs promote progression of residual HCC cells after sublethal heat treatment from autophagic survival to proliferation via HGF/c-Met signaling. A combined treatment regimen of inhibiting autophagy and c-Met signaling could be used to suppress tumor progression of residual HCC after incomplete thermal ablation.
机译：对于大中型肝细胞癌（HCC），消融后常会发生镜下残留肿瘤，导致随访期间早期侵袭性复发或晚期复发。微观上残留的HCC细胞如何在亚致死性热应激下生存并快速生长的机理仍知之甚少。使HCC细胞经受亚致死性热处理，并与来自活化HSC（HSC-CM）的条件培养基共培养。分析了热处理后的残留HCC细胞的细胞增殖，细胞自噬参数和信号通路激活的变化。对肝癌原位模型进行部分热消融，并研究了联合治疗方案的抗肿瘤作用。 HCC细胞通过激活自噬而在亚致死热应激条件下存活。 HSC-CM可在24小时内增强自噬存活，然后通过HGF / c-Met信号传导促进热处理后的残留HCC细胞的增殖。自噬或c-Met的抑制作用增加了热处理的残留HCC细胞的凋亡，并逆转了HSC-CM的保护作用。 HGF通过HGF / c-Met / ERK信号以及ATG5 / Beclin1或cyclinD1的下游成分调节热处理后残留HCC自噬存活或增殖中的生物学状态。在动物模型中，通过抑制自噬，减少增殖和增加凋亡，与c-Met抑制剂联合使用抑制自噬可显着阻止不完全热消融后残余HCC的肿瘤进展。亚致死热处理后，活化的HSC促进残余HCC细胞从自噬生存到通过HGF / c-Met信号传导增殖。抑制自噬和c-Met信号传导的联合治疗方案可用于抑制不完全热消融后残留HCC的肿瘤进展。

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