title: Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death. Recent epidemiological data indicate that the mortality rate of HCC will double over the next decades in the USA and Europe. Liver cancer progresses in a large percentage of cases during the clinical course of chronic fibro-inflammatory liver diseases leading to cirrhosis. Therefore, HCC development is regarded as the result of different environmental risk factors each involving different genetic, epigenetic- and chromosomal alterations and gene mutations. During tumour progression, the malignant hepatocytes and the activated hepatic stellate cells are accompanied by cancer-associated fibroblasts, myofibroblasts and immune cells generally called tumour stromal cells. This new and dynamic milieu further enhances the responsiveness of tumour cells towards soluble mediators secreted by tumour stromal cells, thus directly affecting the malignant hepatocytes. This results in altered molecular pathways with cell proliferation as the most important mechanism of liver cancer progression. Given this contextual complexity, it is of utmost importance to characterize the molecular pathogenesis of HCC, and to identify the dominant pathways/drivers and aberrant signalling pathways. This will allow an effective therapy for HCC that should combine strategies affecting both cancer and the tumour stromal cells. This review provides an overview of the recent challenges and issues regarding hepatic stellate cells, extracellular matrix dynamics, liver fibrosis/cirrhosis and therapy, tumour microenvironment and HCC.
authors.affiliation: Department of Experimental and Clinical Medicine, Center for Research, Transfer and High Education, DENOthe, University of Florence, Florence, Italy.
authors.forename: Vinicio
authors.initials: V
authors.lastname: Carloni
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.forename: Krista
authors.initials: K
authors.lastname: Rombouts
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002450:Cell Communication; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D059016:Tumor Microenvironment
keywords: HSC senescence; anticancer treatment; antifibrogenic treatment; deactivated-hepatic stellate cells; extracellular matrix; genomics; hepatocellular carcinoma; in vitro-activated hepatic stellate cells; in vivo-activated hepatic stellate cells; intratumour heterogeneity; secretomics; transcriptome; tumour-stromal microenvironment