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Hepatocellular Carcinoma: Tissue Microenvironment and Precision Medicine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (27 May 2019) | Viewed by 50280

Special Issue Editor

National Institute of Gastroenterology, Saverio de Bellis Research Hospital, Via Turi, 27-70013 Castellana Grotte (BA), Italy
Interests: HCC; CCA; tumor microenvironment; therapy; biomarkers; TGF-beta; notch
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Achieving a satisfactory survival in patients at an advanced stage of hepatocellular carcinoma (HCC) is still an unmet objective. There are a number of reasons for the lack of response to therapy, including major side-effects caused by sorafenib and regorafenib, the only two drugs so far approved for systemic treatment of patients with HCC. On the other hand, there is no doubt that the molecular mechanisms responsible for tumor progression are still poorly understood, also because the underlying chronic liver disease is a heterogenic confounding factor. In the last few years, research into the tissue microenvironment has been gaining ground in view of the cross-talk between the stroma and tumor, responsible for the growth and the progression of HCC. Identification of the pathways is crucial for targeting new drugs in the scenario of a precision medicine approach. In this Special Issue, we will discuss some of the hottest topics in this area, providing new insights in the field.

Prof. Gianluigi Giannelli
Guest Editor

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Keywords

  • microenvironment
  • precision medicine
  • stroma
  • epithelial mesenchimal transition
  • HCC
  • target therapy

Published Papers (9 papers)

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Research

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17 pages, 35456 KiB  
Article
YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role
by Matthias Van Haele, Iván M. Moya, Ruçhan Karaman, Guy Rens, Janne Snoeck, Olivier Govaere, Frederik Nevens, Chris Verslype, Baki Topal, Diethard Monbaliu, Georg Halder and Tania Roskams
Int. J. Mol. Sci. 2019, 20(3), 638; https://doi.org/10.3390/ijms20030638 - 01 Feb 2019
Cited by 43 | Viewed by 5568
Abstract
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding [...] Read more.
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19), combined hepatocellular–cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19 HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19 HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics. Full article
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15 pages, 3073 KiB  
Article
mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence
by Marta Guerrero, Gustavo Ferrín, Manuel Rodríguez-Perálvarez, Sandra González-Rubio, Marina Sánchez-Frías, Víctor Amado, Juan C. Pozo, Antonio Poyato, Rubén Ciria, María D. Ayllón, Pilar Barrera, José L. Montero and Manuel de la Mata
Int. J. Mol. Sci. 2019, 20(2), 336; https://doi.org/10.3390/ijms20020336 - 15 Jan 2019
Cited by 12 | Viewed by 2637
Abstract
(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including [...] Read more.
(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012–2015). MTOR pathway expression was evaluated in the explanted liver by using the “PathScan Intracellular Signalling Array Kit” (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 ± 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (ΔSignal 22.2%; p < 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) ΔSignal 18.2%, p = 0.004; phospho-AMPKa (Thr172) ΔSignal 56.3%, p < 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) ΔSignal 33.3%, p < 0.001 and phospho-S6RP (Ser235/236) ΔSignal 54.6%, p < 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral p = 0.01; peritumoral p = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, p = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates. Full article
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Review

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16 pages, 1011 KiB  
Review
Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis
by Marina Barcena-Varela, Leticia Colyn and Maite G. Fernandez-Barrena
Int. J. Mol. Sci. 2019, 20(10), 2507; https://doi.org/10.3390/ijms20102507 - 21 May 2019
Cited by 45 | Viewed by 6210
Abstract
Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role [...] Read more.
Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients. Full article
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14 pages, 11381 KiB  
Review
Unique Biological Activity and Potential Role of Monomeric Laminin-γ2 as a Novel Biomarker for Hepatocellular Carcinoma: A Review
by Hiroshi Yasuda, Masatoshi Nakagawa, Hirofumi Kiyokawa, Eisaku Yoshida, Toru Yoshimura, Naohiko Koshikawa, Fumio Itoh and Motoharu Seiki
Int. J. Mol. Sci. 2019, 20(1), 226; https://doi.org/10.3390/ijms20010226 - 08 Jan 2019
Cited by 15 | Viewed by 5164
Abstract
Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of [...] Read more.
Laminin (Ln)-332 consists of α3, β3, and γ2 chains, which mediate epithelial cell adhesion to the basement membrane. Ln-γ2, a component of Ln-332, is frequently expressed as a monomer in the invasion front of several types of malignant tissues without simultaneous expression of Ln-α3 and/or Ln-β3 chains. Moreover, monomeric Ln-γ2 induces tumor cell proliferation and migration in vitro. These unique biological activities indicate that monomeric Ln-γ2 could be a candidate biomarker for early cancer surveillance. However, the present immune method for monomeric Ln-γ2 detection can only predict its expression, since no antibody that specifically reacts with monomeric γ2, but not with heterotrimeric γ2 chain, is commercially available. We have, therefore, developed monoclonal antibodies to specifically detect monomeric Ln-γ2, and devised a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). We evaluated its diagnostic value in sera from patients with several digestive cancers, including hepatocellular carcinoma (HCC), and found serum monomeric Ln-γ2 to be a clinically available biomarker for HCC surveillance. The combination of monomeric Ln-γ2 and prothrombin induced by Vitamin K Absence II (PIVKA-II) may be more sensitive for clinical diagnosis of HCC than any currently used combination. Full article
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18 pages, 1414 KiB  
Review
Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics
by Elisa Holstein, Mathias Binder and Wolfgang Mikulits
Int. J. Mol. Sci. 2018, 19(12), 4111; https://doi.org/10.3390/ijms19124111 - 18 Dec 2018
Cited by 21 | Viewed by 6700
Abstract
Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release [...] Read more.
Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release of soluble Axl (sAxl), which is increased in advanced fibrosis and in early-to-late stage HCC in the presence and absence of cirrhosis. Here, we focus on the dynamics of Axl receptor shedding and delineate possible scenarios how Axl signaling might act as driver of fibrosis progression and HCC development. Based on experimental and clinical data, we discuss the consequences of modifying Axl signaling by sAxl cleavage, as well as cellular strategies to escape from antagonizing effects of Axl shedding by the involvement of the hepatic microenvironment. We emphasize a correlation between free Gas6 and free sAxl levels favoring abundant Gas6/Axl signaling in advanced fibrosis and HCC. The raised scenario provides a solid basis for theranostics allowing the use of sAxl as an accurate diagnostic biomarker of liver cirrhosis and HCC, as well as Axl receptor signaling for therapeutic intervention in stratified HCC patients. Full article
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17 pages, 662 KiB  
Review
The Epigenetic Regulation of HCC Metastasis
by Tae-Su Han, Hyun Seung Ban, Keun Hur and Hyun-Soo Cho
Int. J. Mol. Sci. 2018, 19(12), 3978; https://doi.org/10.3390/ijms19123978 - 10 Dec 2018
Cited by 82 | Viewed by 6908
Abstract
Epigenetic alterations, such as histone modification, DNA methylation, and miRNA-mediated processes, are critically associated with various mechanisms of proliferation and metastasis in several types of cancer. To overcome the side effects and limited effectiveness of drugs for cancer treatment, there is a continuous [...] Read more.
Epigenetic alterations, such as histone modification, DNA methylation, and miRNA-mediated processes, are critically associated with various mechanisms of proliferation and metastasis in several types of cancer. To overcome the side effects and limited effectiveness of drugs for cancer treatment, there is a continuous need for the identification of more effective drug targets and the execution of mechanism of action (MOA) studies. Recently, epigenetic modifiers have been recognized as important therapeutic targets for hepatocellular carcinoma (HCC) based on their reported abilities to suppress HCC metastasis and proliferation in both in vivo and in vitro studies. Therefore, here, we introduce epigenetic modifiers and alterations related to HCC metastasis and proliferation, and their molecular mechanisms in HCC metastasis. The existing data suggest that the study of epigenetic modifiers is important for the development of specific inhibitors and diagnostic targets for HCC treatment. Full article
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31 pages, 1325 KiB  
Review
Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy
by Aldona Kasprzak and Agnieszka Adamek
Int. J. Mol. Sci. 2018, 19(12), 3887; https://doi.org/10.3390/ijms19123887 - 05 Dec 2018
Cited by 49 | Viewed by 5152
Abstract
The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality [...] Read more.
The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC. Full article
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21 pages, 990 KiB  
Review
Long Non-Coding RNAs as Mediators of Tumor Microenvironment and Liver Cancer Cell Communication
by Yang-Hsiang Lin, Meng-Han Wu, Chau-Ting Yeh and Kwang-Huei Lin
Int. J. Mol. Sci. 2018, 19(12), 3742; https://doi.org/10.3390/ijms19123742 - 24 Nov 2018
Cited by 50 | Viewed by 5618
Abstract
The tumor microenvironment is an important concept that defines cancer development not only through tumor cells themselves but also the surrounding cellular and non-cellular components, including stromal cells, blood vessels, infiltrating inflammatory cells, cancer stem cells (CSC), cytokines, and growth factors, which act [...] Read more.
The tumor microenvironment is an important concept that defines cancer development not only through tumor cells themselves but also the surrounding cellular and non-cellular components, including stromal cells, blood vessels, infiltrating inflammatory cells, cancer stem cells (CSC), cytokines, and growth factors, which act in concert to promote tumor cell survival and metastasis. Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Poor prognosis is largely attributable to the high rate of tumor metastasis, highlighting the importance of identifying patients at risk in advance and developing novel therapeutic targets to facilitate effective intervention. Long non-coding RNAs (lncRNA) are a class of non-protein coding transcripts longer than 200 nucleotides frequently dysregulated in various cancer types, which have multiple functions in widespread biological processes, including proliferation, apoptosis, metastasis, and metabolism. lncRNAs are involved in regulation of the tumor microenvironment and reciprocal signaling between cancer cells. Targeting of components of the tumor microenvironment or cancer cells has become a considerable focus of therapeutic research and establishing the effects of different lncRNAs on this network should aid in the development of effective treatment strategies. The current review provides a summary of the essential properties and functional roles of known lncRNAs associated with the tumor microenvironment in HCC. Full article
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17 pages, 787 KiB  
Review
Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma
by Yasuo Tanaka, Ryosuke Tateishi and Kazuhiko Koike
Int. J. Mol. Sci. 2018, 19(10), 3070; https://doi.org/10.3390/ijms19103070 - 08 Oct 2018
Cited by 43 | Viewed by 5492
Abstract
Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects [...] Read more.
Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects cancer cell signaling pathways, which alters growth, migration, and angiogenesis and could facilitate tumorigenesis. This dysregulation of proteoglycans has been implicated in the pathogenesis of diseases such as hepatocellular carcinoma (HCC) and the underlying mechanism has been studied extensively. This review summarizes the current knowledge of the roles of proteoglycans in the genesis and progression of HCC. It focuses on well-investigated proteoglycans such as serglycin, syndecan-1, glypican 3, agrin, collagen XVIII/endostatin, versican, and decorin, with particular emphasis on the potential of these factors as biomarkers and therapeutic targets in HCC regarding the future perspective of precision medicine toward the “cure of HCC”. Full article
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