Loneker Abigail E, Wells Rebecca G
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Physical Sciences in Oncology Center PSOC@Penn, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cancers (Basel). 2021 Aug 25;13(17):4275. doi: 10.3390/cancers13174275.
Hepatocellular carcinoma (HCC) is the second most deadly primary cancer in the world and is thus a major global health challenge. HCC primarily develops in patients with an underlying chronic liver disease, the vast majority with advanced cirrhosis, characterized by increased matrix deposition and liver stiffness. Liver stiffness is highly associated with cancer development and poor patient outcome and is measured clinically to assess cancer risk; cirrhotic livers greatly exceed the threshold stiffness shown to alter hepatocyte cell behavior and to increase the malignancy of cancer cells. Recent studies have shown that cirrhotic liver cells have highly irregular nuclear morphologies and that nuclear deformation mediates mechanosensitive signaling. Separate research has shown that nuclear deformation can increase genetic instability and the accumulation of DNA damage in migrating cancer cells. We hypothesize that the mechanical changes associated with chronic liver disease are drivers of oncogenesis, activating mechanosensitive signaling pathways, increasing rates of DNA damage, and ultimately inducing malignant transformation.
肝细胞癌（HCC）是全球第二大致命性原发性癌症，因此是一项重大的全球健康挑战。HCC主要发生在患有潜在慢性肝病的患者中，绝大多数患者患有晚期肝硬化，其特征是基质沉积增加和肝脏硬度增加。肝脏硬度与癌症发展及患者不良预后高度相关，临床上通过测量肝脏硬度来评估癌症风险；肝硬化肝脏的硬度大大超过了已证实会改变肝细胞行为并增加癌细胞恶性程度的阈值硬度。最近的研究表明，肝硬化肝细胞具有高度不规则的核形态，并且核变形介导机械敏感信号传导。另一项研究表明，核变形会增加迁移癌细胞中的遗传不稳定性和DNA损伤的积累。我们假设，与慢性肝病相关的机械变化是肿瘤发生的驱动因素，激活机械敏感信号通路，增加DNA损伤率，并最终诱导恶性转化。
