Fibrosis-dependent mechanisms of hepatocarcinogenesis

StephenW

http://onlinelibrary.wiley.com/doi/10.1002/hep.25670/abstract
Fibrosis-dependent mechanisms of hepatocarcinogenesis†

    David Y. Zhang,
    Scott L. Friedman†,*

Article first published online: 29 JUN 2012

DOI: 10.1002/hep.25670
Email: Scott L. Friedman ([email protected])

*Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70C, New York, NY 10029

    †

    Potential conflict of interest: Nothing to report.

Abstract

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. (HEPATOLOGY 2012)

StephenW

肝癌肝纤维化依赖机制†

    张大卫华，
    斯科特·弗里德曼†*

条第一网上公布：2012年6月29日

DOI：10.1002/hep.25670
电子邮件：斯科特弗里德曼（scott.friedman@ mssm.edu）

*科肝病，1123箱，西奈山医学院，1425麦迪逊大道，客房11-70C，纽约，纽约10029

    †

    潜在的利益冲突：任何报告。

抽象

肝细胞癌（HCC）是世界范围内癌症死亡率上升的原因，作出澄清的一个紧迫的优先事项的基础机制。肝脏反应损伤是独一无二的，同时进行再生和纤维化。肝癌发生在这两个不同的反应的情况下，导致癌变的独特途径。在这次审查中，我们强调依赖于肝肿瘤的途径，或者是增强，纤维化。激活的肝星状细胞驱动纤维化，改变细胞外基质的成分。矩阵的数量和刚度也增加，提供结合生长因子的水库。除了促进血管生成，这些因素都可能提高癌前肝细胞和激活的肝星状细胞的生存。肝纤维化的变化，也可以调节肝脏炎性细胞的活性，降低自然杀伤活性和自然杀伤T细胞，通常有助于肿瘤监视。炎症信号，包括端粒酶激活和活性氧释放，最终导致癌症，这些途径增效。澄清纤维化依赖瘤机制，将有助于理顺作为一项战略，以预防和治疗肝癌的抗肝纤维化治疗。 （2012年肝病）