[Frontiers in Bioscience S5, 217-230, January 1, 2013]

Cellular basis of hepatic fibrosis and its role in inflammation and cancer

Peri Kocabayoglu1, Scott L. Friedman1

1Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA


1. Abstract
2. Introduction
3. Mechanisms of hepatic stellate cell activation - Overview
3.1. Hepatic stellate cell activation
3.1.1. Initiation
3.1.2. Perpetuation
3.1.3. Resolution
4. Permissive effects of fibrosis and the microenvironment on HCC development
4.1. Enhanced oxidative stress and DNA damage
4.2. Increased matrix stiffness promotes cancer
4.2.1. Composition of ECM in the setting of fibrosis
4.3. Matrix bound growth factors promote cancer
4.4. Telomere shortening
4.5. Enhanced inflammation associated with fibrosis
4.6. Reduced NK-mediated killing of tumor cells
4.7. Stromal Hedgehog signaling
4.8. Activated stellate cells may promote stem cell expansion
5. Perspectives
6. References


Multiple etiologies of liver injury can lead to fibrosis, which results from an imbalance between production and resorption of extracellular matrix. Hepatic stellate cells (HSCs), resident vitamin A storing cells, play a vital role in the response to injury. Upon activation, HSCs orchestrate the responsiveness of the liver to different types of injury, leading to deposition of excessive scar matrix into the interstitium as a wound-healing response. Quantitatively and qualitatively, the altered extracellular matrix (ECM) provides a permissive milieu for the development of cellular dysplasia and ultimately hepatocellular carcinoma (HCC). There is a range of underlying mechanisms that contribute to progression of fibrosis to HCC. As the functional complexity of HSC activation and its roles in inflammation, immune responses, angiogenesis, and proliferation are being clarified, new advances in therapeutic options for patients with chronic liver disease are emerging.