Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyRole of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma
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
References (149)
- et al.
Hepatocellular carcinoma
Lancet
(2003) - et al.
Targeted therapies for hepatocellular carcinoma
Gastroenterology
(2011) - et al.
Accessories to the crime: functions of cells recruited to the tumor microenvironment
Cancer Cell
(2012) - et al.
Inflammation and the development of pancreatic cancer
Surg Oncol
(2002) - et al.
Matrix crosslinking forces tumor progression by enhancing integrin signalling
Cell
(2009) - et al.
Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion
Cell
(2005) - et al.
Molecular characterization of the tumor microenvironment in breast cancer
Cancer Cell
(2004) - et al.
The protein kinase B/Akt signalling pathway in human malignancy
Cell Signal
(2002) - et al.
Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors
Cancer Lett
(2005) - et al.
Autocrine VEGF signalling synergizes with EGFR in tumor cells to promote epithelial cancer development
Cell
(2010)
Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment
Cancer Cell
Serum levels of cytokines in chronic liver diseases
Gastroenterology
Expression of interleukin-18, interferon-gamma and interleukin-10 in hepatocellular carcinoma
Immunol Lett
The hepatitis B viral X protein activates NF-kappaB signalling pathway through the up-regulation of TBK1
FEBS Lett
Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation
Cancer Cell
Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4
Cancer Cell
Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats
J Hepatol
TGFbeta in cancer
Cell
Transforming growth factor betas and their signalling receptors in human hepatocellular carcinoma
Am J Surg
Reduced expression of fibroblast growth factor receptor 2IIIb in hepatocellular carcinoma induces a more aggressive growth
Am J Pathol
Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor
Hepatology
Openings between defective endothelial cells explain tumor vessel leakiness
Am J Pathol
Costimulation by extracellular matrix proteins determines the response to TCR ligation
Cell Immunol
Overexpression of romo1 promotes production of reactive oxygen species and invasiveness of hepatic tumor cells
Gastroenterology
Autophagy-related gene 7 (ATG7) and reactive oxygen species/extracellular signal-regulated kinase regulate tetrandrine-induced autophagy in human hepatocellular carcinoma
J Biol Chem
Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients
Gastroenterology
Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients
J Hepatol
Absence of CD83-positive mature and activated dendritic cells at cancer nodules from patients with hepatocellular carcinoma: relevance to hepatocarcinogenesis
Cancer Lett
High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection
Hum Pathol
Global cancer statistics
CA Cancer J Clin
Sorafenib in advanced hepatocellular carcinoma
N Engl J Med
Pten in stromal fibroblasts suppresses mammary epithelial tumours
Nature
TGF-beta signalling in fibroblasts modulates the oncogenic potential of adjacent epithelia
Science
Resection and liver transplantation for hepatocellular carcinoma
Semin Liver Dis
Recurrence of hepatocellular carcinoma
N Engl J Med
Gene expression in fixed tissues and outcome in hepatocellular carcinoma
N Engl J Med
Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data
Proc Natl Acad Sci U S A
Focal gains of VEGFA and molecular classification of hepatocellular carcinoma
Cancer Res
Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets
Hepatology
Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma
Cancer Res
EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma
Cancer Res
A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells
Nat Med
New strategies in hepatocellular carcinoma: genomic prognostic markers
Clin Cancer Res
Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress
Biol Chem
The extracellular matrix: a dynamic niche in cancer progression
J Cell Biol
Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo
Nat Med
Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy
Cancer Discov
Breast-cancer stromal cells with TP53 mutations and nodal metastases
N Engl J Med
Evolution of the cancer genome
Nat Rev Genet
Trophic macrophages in development and disease
Nat Rev Immunol
Cited by (582)
Abnormal metabolism in hepatic stellate cells: Pandora's box of MAFLD related hepatocellular carcinoma
2024, Biochimica et Biophysica Acta - Reviews on CancerImmune Effects of Intra-Arterial Liver-Directed Therapies
2024, Journal of Vascular and Interventional RadiologyBiomechanical forces and force-triggered drug delivery in tumor neovascularization
2024, Biomedicine and PharmacotherapyMicroRNAs as the critical regulators of tumor angiogenesis in liver cancer
2023, Pathology Research and Practice
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.