近日，美国斯坦福大学Natalie J. Török及其研究组发现，基质粘弹性促进硬化前肝脏的肝癌进展。相关论文于2024年1月31日在线发表在《自然》杂志上。
研究人员表示，2型糖尿病是肝细胞癌（HCC）的主要风险因素。细胞外基质（ECM）力学的变化有助于癌症的发展，而硬度的增加已知会促进肝硬化状态下HCC的进展。2型糖尿病的特点是ECM中高级糖化终产物（AGE）的积累，但这对非肝硬化状态下的HCC有何影响尚不清楚。
研究人员发现在患者和动物模型中，AGE会促进胶原结构的变化并增强ECM的粘弹性，使粘度耗散更大、应力松弛更快，但不会改变硬度。高AGE和粘弹性与致癌β-catenin信号结合会促进HCC的诱导，而抑制AGE的产生、重组AGE清除受体AGER1或断开AGE介导的胶原交联会降低粘弹性和HCC的生长。基质分析和计算建模表明，AGE捆绑胶原基质的互连性较低，纤维长度较短，异质性较大，从而增强了粘弹性。
从机理上讲，动物研究和三维细胞培养表明，增强的粘弹性可通过整合素-β1–张力蛋白-1–YAP机械传导途径促进HCC细胞的增殖和侵袭。这些结果表明，AGE介导的结构变化增强了ECM的粘弹性，而粘弹性可促进体内癌症的进展，与硬度无关。
附：英文原文
Title: Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver
Author: Fan, Weiguo, Adebowale, Kolade, Vncza, Lrnd, Li, Yuan, Rabbi, Md Foysal, Kunimoto, Koshi, Chen, Dongning, Mozes, Gergely, Chiu, David Kung-Chun, Li, Yisi, Tao, Junyan, Wei, Yi, Adeniji, Nia, Brunsing, Ryan L., Dhanasekaran, Renumathy, Singhi, Aatur, Geller, David, Lo, Su Hao, Hodgson, Louis, Engleman, Edgar G., Charville, Gregory W., Charu, Vivek, Monga, Satdarshan P., Kim, Taeyoon, Wells, Rebecca G., Chaudhuri, Ovijit, Trk, Natalie J.
Issue&Volume: 2024-01-31
Abstract: Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
DOI: 10.1038/s41586-023-06991-9
Source: https://www.nature.com/articles/s41586-023-06991-9
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
