Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

Abstract

Primary liver cancer (PLC) includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma and is the sixth most common cancer worldwide with poor prognosis. PLC is characterized by an abundant stromal reaction in which cancer-associated fibroblasts (CAFs) are one of the major stromal components. Solid evidence has demonstrated the crucial role of CAFs in tumor progression, and CAF abundance is often correlated with poor clinical outcomes. Although CAFs are regarded as an attractive and promising target for PLC treatment, a poor understanding of CAF origins and heterogeneity and a lack of specific CAF markers are the major hurdles to efficient CAF-specific therapy. In this review, we examine recent advances in the understanding of CAF diversity in the context of biomarkers, subtypes, and functions in PLC. The regulatory roles of CAFs in extracellular matrix remodeling, metastasis, cancer stemness, and therapeutic resistance are summarized. With an increasing link between CAF abundance and reduced antitumor immune responses, we provide updated knowledge on the crosstalk between CAFs and immune cells within the tumor microenvironment, which leads to immune resistance. In addition, we present current CAF-targeted therapies and describe some future perspectives. A better understanding of CAF biology will shed light on a novel therapeutic strategy against PLC. Primary liver cancer (PLC) includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma and is the sixth most common cancer worldwide with poor prognosis. PLC is characterized by an abundant stromal reaction in which cancer-associated fibroblasts (CAFs) are one of the major stromal components. Solid evidence has demonstrated the crucial role of CAFs in tumor progression, and CAF abundance is often correlated with poor clinical outcomes. Although CAFs are regarded as an attractive and promising target for PLC treatment, a poor understanding of CAF origins and heterogeneity and a lack of specific CAF markers are the major hurdles to efficient CAF-specific therapy. In this review, we examine recent advances in the understanding of CAF diversity in the context of biomarkers, subtypes, and functions in PLC. The regulatory roles of CAFs in extracellular matrix remodeling, metastasis, cancer stemness, and therapeutic resistance are summarized. With an increasing link between CAF abundance and reduced antitumor immune responses, we provide updated knowledge on the crosstalk between CAFs and immune cells within the tumor microenvironment, which leads to immune resistance. In addition, we present current CAF-targeted therapies and describe some future perspectives. A better understanding of CAF biology will shed light on a novel therapeutic strategy against PLC. SummaryAccumulating evidence provides the critical roles of cancer-associated fibroblasts in extracellular matrix remodeling, metastasis, cancer stemness, immune modulation, and therapeutic resistance. A better understanding of cancer-associated fibroblast biology will shed light on a novel therapeutic strategy against primary liver cancer. Accumulating evidence provides the critical roles of cancer-associated fibroblasts in extracellular matrix remodeling, metastasis, cancer stemness, immune modulation, and therapeutic resistance. A better understanding of cancer-associated fibroblast biology will shed light on a novel therapeutic strategy against primary liver cancer. Primary liver cancer (PLC) ranks sixth in cancer incidence and third worldwide as a leading cause of cancer-related death, with an estimated incidence of more than 1 million cases by 2025.1Fitzmaurice C. Allen C. Barber R.M. et al.Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study.JAMA Oncol. 2017; 3: 524-548Crossref PubMed Scopus (2735) Google Scholar Compared with other malignancies, hepatocellular carcinoma (HCC) with cholangiocarcinoma (CCA) are by far the second-most common, accounting for approximately 70% and 15% of cases, respectively, and represents both ends of the spectrum of primary malignant tumors.2Banales J.M. Marin J.J. Lamarca A. et al.Cholangiocarcinoma 2020: the next horizon in mechanisms and management.Nat Rev Gastroenterol Hepatol. 2020; 17: 557-588Crossref PubMed Scopus (661) Google Scholar HCC is derived from the malignant transformation of hepatocytes. Chronic hepatitis B virus and hepatitis C virus infections are considered the most prominent risk factors for HCC development, accounting for more than half of cases.3Llovet J.M. Castet F. Heikenwalder M. et al.Immunotherapies for hepatocellular carcinoma.Nat Rev Clin Oncol. 2022; 19: 151-172Crossref PubMed Scopus (183) Google Scholar Additionally, alcohol intake or chronic inflammatory conditions, such as nonalcoholic steatohepatitis (NASH) associated with metabolic syndrome or diabetes mellitus, are becoming the fastest growing causes of HCC, particularly in western countries. Reports on mutational signatures have also demonstrated that aristolochic acid and tobacco may be potential pathogenetic factors associated with HCC.4Schulze K. Imbeaud S. Letouzé E. et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511Crossref PubMed Scopus (1025) Google Scholar Because of the delayed diagnostic time of HCC, most patients are discovered and considered as inoperable.5Trifylli E.M. Koustas E. Papadopoulos N. et al.An insight into the novel immunotherapy and targeted therapeutic strategies for hepatocellular carcinoma and cholangiocarcinoma.Life. 2022; 12: 665Crossref PubMed Scopus (5) Google Scholar CCA is thought to originate from the malignant transformation of cholangiocytes and is the most aggressive malignant tumor of the biliary tract. CCA is generally classified as intrahepatic and extrahepatic.6Dondossola D. Ghidini M. Grossi F. et al.Practical review for diagnosis and clinical management of perihilar cholangiocarcinoma.World J Gastroenterol. 2020; 26: 3542-3561Crossref PubMed Scopus (17) Google Scholar Among these, intrahepatic cholangiocarcinoma (iCCA) together with HCC is considered one of the most common PLC. Similar to HCC, CCA also develops from hepatitis B and C virus infection and unresolved inflammatory conditions, including obesity, diabetic mellitus, and congenital hepatic fibrosis. Specifically, the main predisposing condition for CCA in western countries is primary sclerosing cholangitis.7Paillet J. Plantureux C. Lévesque S. et al.Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma.J Exp Med. 2021; 218e20200853Crossref PubMed Scopus (9) Google Scholar Notably, in Southeast Asia, liver fluke infections have the highest correlated risk of CCA, which spreads to the bile ducts, gallbladder, and liver parenchyma and causes chronic infection and inflammation.8Qian M.B. Chen Y.D. Liang S. et al.The global epidemiology of clonorchiasis and its relation with cholangiocarcinoma.Infect Dis Poverty. 2012; 1: 1-12Crossref PubMed Scopus (113) Google Scholar Additionally, intrahepatic stones could also be one of the major causes of iCCA. For patients with HCC receiving curative-intent treatments, the 5-year overall survival rate is more than 50%, whereas for patients with iCCA receiving curative-intent surgery, the 5-year overall survival rate is only approximately 5%–17%, suggesting that patients with iCCA might have a worse prognosis than those with HCC. Locoregional therapies could be an alternative option for patients who cannot receive surgical intervention. Systemic therapy is also recommended for advanced liver cancer.9Lee Y.T. Wang J.J. Luu M. et al.Comparison of clinical features and outcomes between intrahepatic cholangiocarcinoma and hepatocellular carcinoma in the United States.Hepatology. 2021; 74: 2622-2632Crossref PubMed Scopus (14) Google Scholar However, in combination with the high degree of malignancy and the severity of neighboring invasion, the optimal management of HCC and CCA remains an extreme challenge and is long in duration. During hepatocarcinogenesis, persistent liver damage and advanced stage of liver fibrosis are key drivers. To be noted, more than 90% of HCC cases develop from a background of liver cirrhosis, and approximately one-third of patients with liver cirrhosis ultimately develop HCC.10El-Serag H.B. Hepatocellular carcinoma: recent trends in the United States.Gastroenterology. 2004; 127: S27-S34Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar Indeed, an increasing number of studies suggest that the reconstruction of the tumor microenvironment (TME), a suitable environment for tumor cells, promotes tumor progression.11Zhang J. Gu C. Song Q. et al.Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma.Cell Biosci. 2020; 10: 1-15Crossref PubMed Scopus (0) Google Scholar In HCC, the reciprocal crosstalk among the TME, which includes cancer-associated fibroblasts immune cells, cells, extracellular matrix and HCC cells, metastasis, and J. Gu C. Song Q. et al.Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma.Cell Biosci. 2020; 10: 1-15Crossref PubMed Scopus (0) Google Scholar also are a of fibroblasts in the tumor with and fibroblast are the main of cells, which is one of the critical and abundant in the TME, and have in the of C. K. et of cancer-associated fibroblasts and roles in the progression, and therapy of hepatocellular Oncol. 12: PubMed Scopus Google Scholar to the the origins of CAFs in HCC and CCA could be from a of hepatic cells have as the of hepatic in Liang S. et al.The role of cancer-associated fibroblasts in hepatocellular carcinoma and the of Oncol. 2021; Scopus Google Scholar are cells that with cells and hepatic C. K. et cells in liver development, and Clin PubMed Scopus Google Scholar During chronic liver and to the and into of hepatic Rev Gastroenterol Hepatol. 2017; PubMed Scopus Google Scholar that to more than of in liver fibrosis and biliary liver et hepatic cells as to liver fibrosis of its Scopus Google Scholar et et to tumor by cells to cancer-associated Exp Clin PubMed Scopus Google Scholar that HCC cells which the of into and and CAFs high of that HCC in Wang et C. 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F. et of cholangiocarcinoma by cancer-associated fibroblast 2021; Full Text Full Text PDF PubMed Scopus Google Scholar of CAF that most CAFs an including and of suggesting an whereas than the markers of fibroblasts in iCCA. Additionally, of and iCCA that the with the most with tumor cells, and associated with survival and risk in S. A. F. et of cholangiocarcinoma by cancer-associated fibroblast 2021; Full Text Full Text PDF PubMed Scopus Google Scholar are in the and the of the biliary and of biliary PubMed Scopus Google Scholar be from by of and with high of and to the of hepatic the of to the major of CAFs the of liver and liver et hepatic cells and fibroblasts to liver fibrosis in Hepatol. 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