a Zhongshan Hospital Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Liver Cancer Institute , Shanghai , China.
Int J Hyperthermia. 2019;36(1):253-263. doi: 10.1080/02656736.2018.1558459. Epub 2019 Jan 31.
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.
中等大小肝细胞癌（HCC）热消融后常残留微小肿瘤，导致随访期间早期侵袭性复发或晚期复发。微小残留 HCC 细胞如何在亚致死热应激下存活并迅速生长的机制尚不清楚。
将 HCC 细胞暴露于亚致死热疗并与激活的肝星状细胞（HSC）的条件培养基（HSC-CM）共培养。分析热疗后残留 HCC 细胞增殖、自噬参数和信号通路激活的变化。对 HCC 原位模型进行部分热消融，并研究联合治疗方案的抗肿瘤作用。
HCC 细胞通过自噬激活来存活亚致死热应激。HSC-CM 在 24 小时内增强自噬存活，然后通过 HGF/c-Met 信号促进热疗后残留 HCC 细胞的增殖。自噬或 c-Met 抑制增加了热疗后残留 HCC 细胞的凋亡，并逆转了 HSC-CM 的保护作用。HGF 通过 HGF/c-Met/ERK 信号及其下游 ATG5/Beclin1 或 cyclinD1 成分调节自噬存活或热疗后残留 HCC 细胞的增殖中的生物学状态。在动物模型中，通过抑制自噬联合 c-Met 抑制剂，可通过抑制自噬、减少增殖和增加凋亡来显著阻止不完全热消融后残留 HCC 的肿瘤进展。
激活的 HSCs 通过 HGF/c-Met 信号促进亚致死热疗后残留 HCC 细胞从自噬存活到增殖的进展。抑制自噬和 c-Met 信号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。
