Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hepatology. 2012 Aug;56(2):769-75. doi: 10.1002/hep.25670. Epub 2012 Jun 29.
Hepatocellular carcinoma (HCC) is a rising worldwide cause of cancer mortality, making the elucidation of its underlying mechanisms an urgent priority. The liver is unique in its response to injury, simultaneously undergoing regeneration and fibrosis. HCC occurs in the context of these two divergent responses, leading to distinctive pathways of carcinogenesis. In this review we highlight pathways of liver tumorigenesis that depend on, or are enhanced by, fibrosis. Activated hepatic stellate cells drive fibrogenesis, changing the composition of the extracellular matrix. Matrix quantity and stiffness also increase, providing a reservoir for bound growth factors. In addition to promoting angiogenesis, these factors may enhance the survival of both preneoplastic hepatocytes and activated hepatic stellate cells. Fibrotic changes also modulate the activity of inflammatory cells in the liver, reducing the activity of natural killer and natural killer T cells that normally contribute to tumor surveillance. These pathways synergize with inflammatory signals, including telomerase reactivation and reactive oxygen species release, ultimately resulting in cancer. Clarifying fibrosis-dependent tumorigenic mechanisms will help rationalize antifibrotic therapies as a strategy to prevent and treat HCC.
肝细胞癌（HCC）是全球癌症死亡率上升的一个原因，阐明其潜在机制是当务之急。肝脏在应对损伤时具有独特的反应，同时进行再生和纤维化。HCC 发生在这两种不同反应的背景下，导致了独特的致癌途径。在这篇综述中，我们强调了依赖于纤维化或受纤维化增强的肝肿瘤发生途径。激活的肝星状细胞驱动纤维化，改变细胞外基质的组成。基质数量和硬度也增加，为结合的生长因子提供了储存库。除了促进血管生成外，这些因子还可能增强肿瘤前肝细胞和激活的肝星状细胞的存活。纤维化改变还调节肝脏中炎症细胞的活性，降低通常有助于肿瘤监测的自然杀伤细胞和自然杀伤 T 细胞的活性。这些途径与炎症信号协同作用，包括端粒酶的重新激活和活性氧的释放，最终导致癌症。阐明依赖于纤维化的肿瘤发生机制将有助于合理化抗纤维化治疗作为预防和治疗 HCC 的策略。
