Gastroenterology

Gastroenterology

Volume 144, Issue 3, March 2013, Pages 512-527
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma

https://doi.org/10.1053/j.gastro.2013.01.002Get rights and content

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide, and its incidence is increasing. Despite the significant improvement in management of HCC over the past 30 years, there are no effective chemoprevention strategies, and only one systemic therapy has been approved for patients with advanced tumors. This drug, sorafenib, acts on tumor cells and the stroma. HCC develops from chronically damaged tissue that contains large amounts of inflammation and fibrosis, which also promote tumor progression and resistance to therapy. Increasing our understanding of how stromal components interact with cancer cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.

Section snippets

Importance of the Tumor Microenvironment

The development and progression of HCC is a multistage process. A chronic insult (eg, HCV, HBV, and alcohol) induces liver injury through reactive oxygen species (ROS) production, cellular DNA damage, endoplasmic reticulum stress, and necrosis of damaged hepatocytes. Most HCCs arise in the setting of chronic hepatitis induced by HCV or HBV infection. HCV is a single-stranded RNA virus that cannot integrate into the host genome but triggers an immune-mediated inflammatory response that promotes

Relevance of the Microenvironment in Other Malignancies

The link between inflammation and generation of a preneoplastic milieu has been reported in many diseases, such as in the development of colorectal and pancreatic carcinomas in the context of inflammatory bowel disease and chronic pancreatitis, respectively.19 Once the cancer has been established, the contribution of the microenvironment to the regulation of tumor behavior has been well recognized for other malignancies, including breast, lung, and pancreatic carcinomas.5

Abnormal ECM production

Biological Processes Involved in the Tumor Microenvironment

The precancerous milieu of chronic liver disease is characterized by neoangiogenesis, including several vascular abnormalities such as arterialization and sinusoidal capillarization, as well as inflammation and fibrosis. These biological processes become more pronounced with progression of liver failure, in which the incidence of cancer increases exponentially (Figure 2). Synchronous events occurring in this setting also include hypoxia, oxidative stress, and autophagy.

Cellular Components of the HCC Microenvironment

HCC usually arises in a severely perturbed microenvironment that hastens dysfunction of epithelial cells and malignant transformation. Targeting the components of the microenvironment therefore emerges as a rational preventive strategy (Figure 1). Here we describe the main cellular components in the microenvironment and identify potential molecular targets for therapies.

Animal Models to Study the Tumor Microenvironment

Liver carcinogenesis is a multistep process with several cellular and mechanical deregulations that eventually lead to malignant transformation of hepatocytes. Numerous mouse models successfully produce HCC; however, not all of them mimic the pathogenic sequence of human HCC that starts with fibrosis, cirrhosis, angiogenesis, and preneoplastic nodules before HCC develops. There are 4 main categories of murine HCC models: chemically induced, oncogene driven, xenograft, and genetically modified.

Prognostic Relevance of the Nontumor Adjacent Tissue in Patients With HCC

Genomic studies have shown the relevance of the tumor microenvironment in predicting outcome in patients with HCC (Table 1). A 36-gene signature originating from the surrounding non-neoplastic liver tumor was reported to predict multicentric occurrence or late recurrence in patients with HCV-related HCC.129 We identified a poor prognosis signature driven by late recurrence originating from the adjacent cirrhotic tissue in patients with early HCCs using 2 different patient cohorts.10 The

Targeting the Tumor Stroma: A Promising Challenge for New Therapies

In recent years, the tumor stroma has emerged as a critical target for therapy in patients with preneoplastic conditions or established HCC (Figure 4). Modulators of different biological processes, including inflammation, fibrosis, angiogenesis, and signals of proliferation and survival, might be effective in the prevention and primary treatment of early HCC. Due to the implications of inflammatory pathways (eg, IL-6, NF-κB) and EGF signaling in cirrhotic patients at high risk for developing

Conclusion and Future Prospects

HCC commonly arises in a damaged organ featured by extensive inflammation and fibrosis. Different players, including immune cells, hepatic stellate cells, and macrophages, react to liver injury by producing cytokines and components of the ECM, which promote angiogenesis, and survival of damaged hepatocytes or cancer stem cells. This regenerative response favors the accumulation of mutations and epigenetic aberrations, which lead to malignant transformation of preneoplastic nodules. The

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    Conflicts of interest The authors disclose no conflicts.

    Funding J.M.L. is supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986), European Commission Framework Programme 7 (HEPTROMIC, proposal 259744), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2010-16055), and the Asociación Española Contra el Cáncer. S.L.F. is supported by National Institutes of Health grants RO1DK56621, K05AA01840, R01AA020709, and P20AA017067.

    Authors share co-first authorship.

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