Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is ...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.展开更多
目的探讨人肝细胞肝癌组织(hepatocellular carcinoma,HCC)中激活转录因子3(signal transducer and activa-tor of transcription 3,STAT3)的表达及其在肝癌发病中的作用。方法利用免疫组织化学方法检测76例HCC组织中STAT3的表达情况,2...目的探讨人肝细胞肝癌组织(hepatocellular carcinoma,HCC)中激活转录因子3(signal transducer and activa-tor of transcription 3,STAT3)的表达及其在肝癌发病中的作用。方法利用免疫组织化学方法检测76例HCC组织中STAT3的表达情况,29例肝血管瘤患者手术切除标本中的正常肝组织作为正常对照。同时,检测环氧合酶-2(cyclooxygenase-2,COX-2)的表达情况。结果在HCC组织中STAT3表达较高,阳性表达率为68.4%(P<0.05),并与COX-2的表达呈正相关(r=0.683,P<0.05)。HCC组织中STAT3的表达与饮酒史、肿瘤直径<5cm、静脉侵犯、TNM分期Ⅰ、Ⅱ期显著相关(P<0.05)。结论在HCC发生的早期阶段STAT3与COX-2均呈高表达,STAT3/COX-2信号转导通路可能在肝癌发生早期阶段起一定的作用。展开更多
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.
文摘目的探讨人肝细胞肝癌组织(hepatocellular carcinoma,HCC)中激活转录因子3(signal transducer and activa-tor of transcription 3,STAT3)的表达及其在肝癌发病中的作用。方法利用免疫组织化学方法检测76例HCC组织中STAT3的表达情况,29例肝血管瘤患者手术切除标本中的正常肝组织作为正常对照。同时,检测环氧合酶-2(cyclooxygenase-2,COX-2)的表达情况。结果在HCC组织中STAT3表达较高,阳性表达率为68.4%(P<0.05),并与COX-2的表达呈正相关(r=0.683,P<0.05)。HCC组织中STAT3的表达与饮酒史、肿瘤直径<5cm、静脉侵犯、TNM分期Ⅰ、Ⅱ期显著相关(P<0.05)。结论在HCC发生的早期阶段STAT3与COX-2均呈高表达,STAT3/COX-2信号转导通路可能在肝癌发生早期阶段起一定的作用。
