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Cancers
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Theranostic Advances in Hepatobiliary Tumors
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Theranostic Advances in Hepatobiliary Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 82457

Special Issue Editors

Prof. Dr. Matias A. Avila

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Guest Editor
1. Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
2. Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
Interests: hepatocarcinogenesis; cell signaling; differentiation; epigenetics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Carmen Berasain

E-Mail Website
Guest Editor
Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
Interests: molecular mechanisms of liver disease; gene expression; differentiation; splicing; epigenetics; liver cancer
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Andrea Casadei-Gardini

E-Mail Website
Guest Editor
Department of Medical Oncology, University of Modena, 41121 Modena, Italy
Interests: systemic therapy; clinical outcome; immune-inflammation indexes; radiomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Remarkable advancements in the understanding of the molecular and cellular events, leading to the development and progression of hepatobiliary tumors, have been made over the past years. However, these cancers are proving very difficult to harness from therapeutic and diagnostic standpoints. Recently, several new therapies have been approved for hepatobiliary neoplasias. Among these, immunotherapy and novel targeted small molecules have brought new hope in the field. However, their efficacy is still restricted to a subset of hepatocellular carcinoma patients, and their value for the treatment of biliary tumors has not yet been fully established. In the face of these new therapeutic options, physicians are confronted with new challenges, including the accurate diagnosis of biliary tumors, the monitoring of disease progression, and the stratification of patients for appropriate treatments. The identification of new original prognostic or predictive markers (e.g., radiomics or immune-inflammation indexes) will be fundamental for increasing our knowledge and for improving the clinical management of our patients. Moreover, a deeper understanding of the biology of these cancers is needed to identify better targets and combination strategies to avoid endogenous and acquired drug resistances. The investigation of fundamental mechanisms regulating gene expression and cellular differentiation, such as epigenetic events, and the interaction of tumor cells with their stromal microenvironment, may bring to light new targets for therapeutic intervention.

We invite researchers to submit up-to-date original research articles, short communications, and comprehensive review articles on the topic highlighted in this Special Issue of Cancers.

Prof. Matias A. Avila
Prof. Carmen Berasain
Dr. Andrea Casadei-Gardini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatocellular carcinoma
  • cholangiocarcinoma
  • diagnosis
  • prognosis
  • therapy
  • clinical outcome
  • molecular targets

Published Papers (23 papers)

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Research

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10 pages, 2717 KiB  
Article
Establishment and Characterization of a New Human Intrahepatic Cholangiocarcinoma Cell Line LIV27
by Xiwei Ding, Kais Zakharia, Catherine D. Moser, Nellie A. Campbell, Chunling Hu, Nataliya Razumilava, Roongruedee Chaiteerakij, Hassan M. Shaleh, Patricia T. Greipp, Rondell P. Graham, Xiaoping Zou, Vishal S. Chandan and Lewis R. Roberts
Cancers 2022, 14(20), 5080; https://doi.org/10.3390/cancers14205080 - 17 Oct 2022
Viewed by 1985
Abstract
Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this [...] Read more.
Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this study, we report and characterize a new intrahepatic CCA cell line, LIV27, derived from a surgically resected tumor in a 67-year-old Caucasian woman with primary sclerosing cholangitis (PSC). LIV27 cells grow well in collagen-coated flasks or plates with a doubling time of 57.8 h at passage 14. LIV27 cells have high tumorigenicity in nude mice and stain positive for CK7 and CK19, markers that differentiate CCA from hepatocellular carcinoma. Karyotype analysis showed that LIV27 is aneuploid. We established a single-locus short tandem repeat profile for the LIV27 cell line. This newly established cell line will be a useful model for studying the molecular pathogenesis of, and developing novel therapies for, cholangiocarcinoma. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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17 pages, 4093 KiB  
Article
Potential Role of Inflammation-Promoting Biliary Microbiome in Primary Sclerosing Cholangitis and Cholangiocarcinoma
by Katsuyuki Miyabe, Vinay Chandrasekhara, Nicha Wongjarupong, Jun Chen, Lu Yang, Stephen Johnson, Nicholas Chia, Marina Walther-Antonio, Janet Z. Yao, Sean C. Harrington, Cynthia K. Nordyke, John E. Eaton, Andrea A. Gossard, Sharad Oli, Hamdi A. Ali, Sravanthi Lavu, Nasra H. Giama, Fatima A. Hassan, Hawa M. Ali, Felicity T. Enders, Sumera I. Ilyas, Gregory J. Gores, Mark D. Topazian, Purna C. Kashyap and Lewis R. Robertsadd Show full author list remove Hide full author list
Cancers 2022, 14(9), 2120; https://doi.org/10.3390/cancers14092120 - 24 Apr 2022
Cited by 11 | Viewed by 2275
Abstract
Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. Methods: Bile was obtained from 32 patients with [...] Read more.
Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. Methods: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. Results: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups. Conclusions: We identified a unique microbial signature in the bile of patients with increased duration of PSC or with CCA, suggesting a role for microbiota-driven inflammation in the pathogenesis and or progression to perihilar CCA. Further studies are needed to test this hypothesis. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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10 pages, 1301 KiB  
Communication
Midnolin Regulates Liver Cancer Cell Growth In Vitro and In Vivo
by Soo-Mi Kweon, Gayeoun Kim, Yunseong Jeong, Wendong Huang, Ju-Seog Lee and Keane K. Y. Lai
Cancers 2022, 14(6), 1421; https://doi.org/10.3390/cancers14061421 - 10 Mar 2022
Cited by 4 | Viewed by 2748
Abstract
Hepatocellular carcinoma (HCC) ranks worldwide as one of the most lethal cancers. In spite of the vast existing knowledge about HCC, the pathogenesis of HCC is not completely understood. Discovery of novel genes that contribute to HCC pathogenesis will provide new insights for [...] Read more.
Hepatocellular carcinoma (HCC) ranks worldwide as one of the most lethal cancers. In spite of the vast existing knowledge about HCC, the pathogenesis of HCC is not completely understood. Discovery of novel genes that contribute to HCC pathogenesis will provide new insights for better understanding and treating HCC. The relatively obscure gene midnolin has been studied for over two decades; however, its biological roles are largely unknown. Our study is the first to demonstrate the functional significance of midnolin in HCC/cancer: Midnolin expression correlates with poor prognosis in HCC patients, and suppression of midnolin severely inhibits tumorigenicity of HCC cells in vitro and in mice and disrupts retinoic acid/lipid metabolism in these cells. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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19 pages, 4325 KiB  
Article
A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy
by Feifei Guo, Olga Estévez-Vázquez, Raquel Benedé-Ubieto, Douglas Maya-Miles, Kang Zheng, Rocío Gallego-Durán, Ángela Rojas, Javier Ampuero, Manuel Romero-Gómez, Kaye Philip, Isioma U. Egbuniwe, Chaobo Chen, Jorge Simon, Teresa C. Delgado, María Luz Martínez-Chantar, Jie Sun, Johanna Reissing, Tony Bruns, Arantza Lamas-Paz, Manuel Gómez del Moral, Marius Maximilian Woitok, Javier Vaquero, José R. Regueiro, Christian Liedtke, Christian Trautwein, Rafael Bañares, Francisco Javier Cubero and Yulia A. Nevzorovaadd Show full author list remove Hide full author list
Cancers 2022, 14(1), 192; https://doi.org/10.3390/cancers14010192 - 31 Dec 2021
Cited by 15 | Viewed by 3167
Abstract
Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development [...] Read more.
Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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22 pages, 9021 KiB  
Article
Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
by Chaobo Chen, Hanghang Wu, Hui Ye, Agustín Tortajada, Sandra Rodríguez-Perales, Raúl Torres-Ruiz, August Vidal, Maria Isabel Peligros, Johanna Reissing, Tony Bruns, Mohamed Ramadan Mohamed, Kang Zheng, Amaia Lujambio, Maria J. Iraburu, Leticia Colyn, Maria Ujue Latasa, María Arechederra, Maite G. Fernández-Barrena, Carmen Berasain, Javier Vaquero, Rafael Bañares, Leonard J. Nelson, Christian Trautwein, Roger J. Davis, Eduardo Martinez-Naves, Yulia A. Nevzorova, Alberto Villanueva, Matias A. Avila and Francisco Javier Cuberoadd Show full author list remove Hide full author list
Cancers 2022, 14(1), 78; https://doi.org/10.3390/cancers14010078 - 24 Dec 2021
Cited by 3 | Viewed by 4030
Abstract
Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in [...] Read more.
Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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18 pages, 4912 KiB  
Article
Sulfatase-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
by Ikuo Nakamura, Faizal Z. Asumda, Catherine D. Moser, Yoo Na N. Kang, Jin-Ping Lai and Lewis R. Roberts
Cancers 2021, 13(21), 5279; https://doi.org/10.3390/cancers13215279 - 21 Oct 2021
Cited by 8 | Viewed by 2621
Abstract
Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis [...] Read more.
Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl4) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson’s trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson’s trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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21 pages, 5786 KiB  
Article
Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC
by Vicent Ribas, Laura Conde de la Rosa, David Robles, Susana Núñez, Paula Segalés, Naroa Insausti-Urkia, Estel Solsona-Vilarrasa, José C. Fernández-Checa and Carmen García-Ruiz
Cancers 2021, 13(16), 4091; https://doi.org/10.3390/cancers13164091 - 13 Aug 2021
Cited by 14 | Viewed by 3084
Abstract
The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation [...] Read more.
The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation of different lipid species, and cholesterol has emerged as an important player in NASH development, which has been shown to promote NASH-driven HCC. However, recent findings indicated a tumor suppressor role of cholesterol in liver carcinogenesis and HCC development. Thus, we examined the contribution of hepatic steatosis with or without cholesterol accumulation induced by dietary or genetic approaches in liver tumorigenesis and whether the role of cholesterol in NASH-driven HCC is species-dependent. While diethylnitrosamine (DEN) treatment to rats or mice fed a choline-deficient diet decreased the hepatic steatosis, feeding an atherogenic diet enriched in cholesterol potentiated the liver tumor markers. Similar effects were observed in DEN-treated transgenic SREBP-2 mice but not wild-type (WT) mice fed a regular chow diet. Remarkably, long-term feeding of a high-fat high-cholesterol diet (HFHC) but not a high-fat diet (HFD) to WT mice caused severe NASH with spontaneous progression to HCC. A similar outcome was observed in MUP-uPA transgenic mice fed a HFHC diet, which resulted in increased liver tumors and expression of the genes involved in the immune checkpoints. Ezetimibe treatment ameliorated chronic liver disease and, more importantly, tumor multiplicity in HFHC-fed MUP-uPA mice or DEN-treated WT mice. Thus, these results revealed a differential role of steatosis and cholesterol in NASH-driven HCC and indicated that the tumor-promoter role of cholesterol is species-independent and associated with impaired immunosurveillance. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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16 pages, 1149 KiB  
Article
Uni-, Bi- or Trifocal Hepatocellular Carcinoma in Western Patients: Recurrence and Survival after Percutaneous Thermal Ablation
by Ancelin Preel, Margaux Hermida, Carole Allimant, Eric Assenat, Chloé Guillot, Cecilia Gozzo, Serge Aho-Glele, Georges-Philippe Pageaux, Christophe Cassinotto and Boris Guiu
Cancers 2021, 13(11), 2700; https://doi.org/10.3390/cancers13112700 - 30 May 2021
Cited by 7 | Viewed by 2101
Abstract
Multifocality is usually reported as a pejorative factor after percutaneous thermal ablation (PTA) of HCC but little is known in Western series. Recurrence and survival were extracted from a prospective database of all patients who underwent PTA for ≤3 cm HCC. From [...] Read more.
Multifocality is usually reported as a pejorative factor after percutaneous thermal ablation (PTA) of HCC but little is known in Western series. Recurrence and survival were extracted from a prospective database of all patients who underwent PTA for ≤3 cm HCC. From January 2015 to April 2020, we analyzed 281 patients with unifocal (n = 216), bifocal (n = 46) and trifocal (n = 16) HCC. PTA of bi- and trifocal HCC resulted in a high risk of very early (<6 months) distant recurrence (38.8% and 50%, respectively). Median RFS was 23.3 months (95% CI:18.6–30.4), 7.7 months (95% CI:5.1–11.43, p = 0.002) and 5.2 months (95% CI:3–12.3, p = 0.015), respectively, for uni-, bi- and trifocal HCC groups. In a multivariate analysis, both bifocal (HR = 2.46, p < 0.001) and trifocal (HR = 2.70, p = 0.021) vs. unifocal HCC independently predicted shorter RFS. Median OS in trifocal HCC group was 30.3 months (95 CI:19.3-not reached). Trifocal vs. unifocal HCC independently predicted shorter OS (HR = 3.30, p = 0.008), whereas bifocal vs. unifocal HCC did not (p = 0.27). Naïve patient (HR = 0.42, p = 0.007), AFP > 100 ng/mL (HR = 3.03, p = 0.008), MELD > 9 (HR = 2.84, p = 0.001) and steatotic HCC (HR = 0.12, p = 0.038) were also independent predictors of OS. In conclusion, multifocal HCCs in a Western population have a dramatically increased risk of distant recurrence. OS after PTA of trifocal HCC is significantly below what was expected after a curative treatment. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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17 pages, 2125 KiB  
Article
Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature
by Nicolò Manicardi, Anabel Fernández-Iglesias, Laia Abad-Jordà, Felix Royo, Mikel Azkargorta, Martí Ortega-Ribera, David Sanfeliu-Redondo, Ana Martínez-Alcocer, Felix Elortza, Amelia J. Hessheimer, Constantino Fondevila, Juan José Lozano, Juan Carlos García-Pagán, Jaime Bosch, Francisco Javier Cubero, Agustín Albillos, Javier Vaquero, Juan M. Falcón-Pérez and Jordi Gracia-Sancho
Cancers 2021, 13(11), 2688; https://doi.org/10.3390/cancers13112688 - 29 May 2021
Cited by 18 | Viewed by 4072
Abstract
The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the [...] Read more.
The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the present study aimed at investigating the progression of CLD from an endothelial holistic perspective. RNAseq defined the transcriptome of primary LSECs isolated from three pre-clinical models of advanced CLD, during the progression of the disease, and from fresh human cirrhotic tissue. At each stage of the disease, the effects of LSECs secretome on neighboring cells and proteomic analysis of LSECs-derived extracellular vesicles (EVs) were also determined. CLD was associated with deep common modifications in the transcriptome of LSECs in the pre-clinical models. Pathway enrichment analysis showed predominance of genes related with pro-oncogenic, cellular communication processes, and EVs biogenesis during CLD progression. Crosstalk experiments revealed endothelial EVs as potent angiocrine effectors. The proteome of LSECs EVs showed stage-specific signatures, including over-expression of tropomyosin-1. Proof-of-principle experiments treating cirrhotic HSCs with recombinant tropomyosin-1 suggested de-activating effects. Our data provide the basis for discovering novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced CLD. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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16 pages, 1371 KiB  
Article
Evolution of Surgical Treatment of Colorectal Liver Metastases in the Real World: Single Center Experience in 1212 Cases
by Francesca Ratti, Federica Cipriani, Guido Fiorentini, Valentina Burgio, Monica Ronzoni, Angelo Della Corte, Stefano Cascinu, Francesco De Cobelli and Luca Aldrighetti
Cancers 2021, 13(5), 1178; https://doi.org/10.3390/cancers13051178 - 09 Mar 2021
Cited by 6 | Viewed by 2796
Abstract
Background: In recent years, the treatment of colorectal liver metastases (CRLM) has undergone significant evolution thanks to technical improvements as well as oncological advances, which have been the subject of targeted studies aimed at understanding the details of this heterogeneous disease. The purpose [...] Read more.
Background: In recent years, the treatment of colorectal liver metastases (CRLM) has undergone significant evolution thanks to technical improvements as well as oncological advances, which have been the subject of targeted studies aimed at understanding the details of this heterogeneous disease. The purpose of this study is to put together pieces of this complex scenario by providing an overview of the evolution that has occurred in the context of a single center within a multidisciplinary management approach. Methods: Between 2005 and 2020, 1212 resections for CRLM were performed at the Hepatobiliary Surgery Division of San Raffaele Hospital, Milan. The series was divided into three historical periods, which were compared in terms of disease characteristics and short- and long-term outcomes: Period 1, 2005–2009 (293 cases); Period 2, 2010–2014 (353 cases); Period 3, 2015–2020 (566 cases). The trends for surgical technical complexity, oncological burden of the disease, use of the laparoscopic approach and use of techniques for hepatic hypertrophy were analyzed year by year. Uni- and multivariate analyses were performed to identify factors associated with inclusion to a laparoscopic approach and with long-term prognosis. Results: The number of resections performed over the years progressively increased, with an increase in the number of cases with a high Clinical Risk Score and a high profile of technical complexity. The proportion of cases performed laparoscopically increased, but less rapidly compared to other malignant tumors. The risk of postoperative morbidity and mortality was similar in the three analyzed periods. Long-term survival, stratified by Clinical Risk Score, improved in Period 3, while overall survival remained unchanged. Conclusion: The cultural background, the maturation of technical expertise and the consolidation of the multidisciplinary team have resulted in safe expansion of the possibility to offer a curative opportunity to patients, while continuously implementing into clinical practice evidence provided by the literature. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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20 pages, 2249 KiB  
Article
Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma
by Josep Corominas, Victor Sapena, Marco Sanduzzi-Zamparelli, Cristina Millán, Esther Samper, Neus Llarch, Gemma Iserte, Ferràn Torres, Leonardo G. Da Fonseca, Sergio Muñoz-Martínez, Alejandro Forner, Jordi Bruix, Loreto Boix and María Reig
Cancers 2021, 13(3), 426; https://doi.org/10.3390/cancers13030426 - 23 Jan 2021
Cited by 4 | Viewed by 2759
Abstract
Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. [...] Read more.
Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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14 pages, 1216 KiB  
Article
Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: Results from a Single-Institution Retrospective Analysis
by Ilario Giovanni Rapposelli, Serena De Matteis, Paola Lanuti, Martina Valgiusti, Giulia Bartolini, Paola Ulivi, Giorgia Marisi, Federica Pedica, Valentina Burgio, Giovanni Luca Frassineti, Stefano Cascinu and Andrea Casadei-Gardini
Cancers 2021, 13(2), 213; https://doi.org/10.3390/cancers13020213 - 08 Jan 2021
Cited by 6 | Viewed by 2648
Abstract
Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent [...] Read more.
Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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27 pages, 14235 KiB  
Article
Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis
by Alex Claveria-Cabello, Leticia Colyn, Iker Uriarte, Maria Ujue Latasa, Maria Arechederra, Jose M. Herranz, Laura Alvarez, Jesus M. Urman, Maria L. Martinez-Chantar, Jesus M. Banales, Bruno Sangro, Krista Rombouts, Julen Oyarzabal, Jose J. G. Marin, Carmen Berasain, Matias A. Avila and Maite G. Fernandez-Barrena
Cancers 2020, 12(12), 3748; https://doi.org/10.3390/cancers12123748 - 13 Dec 2020
Cited by 6 | Viewed by 2944
Abstract
Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, [...] Read more.
Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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18 pages, 3931 KiB  
Article
Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma
by Leyre Silva, Josune Egea, Lorea Villanueva, Marta Ruiz, Diana Llopiz, David Repáraz, Belén Aparicio, Aritz Lasarte-Cia, Juan José Lasarte, Marina Ruiz de Galarreta, Amaia Lujambio, Bruno Sangro and Pablo Sarobe
Cancers 2020, 12(11), 3397; https://doi.org/10.3390/cancers12113397 - 16 Nov 2020
Cited by 17 | Viewed by 2483
Abstract
Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on [...] Read more.
Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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17 pages, 5225 KiB  
Article
Direct Antiviral Treatments for Hepatitis C Virus Have Off-Target Effects of Oncologic Relevance in Hepatocellular Carcinoma
by Catia Giovannini, Francesca Fornari, Valentina Indio, Davide Trerè, Matteo Renzulli, Francesco Vasuri, Matteo Cescon, Matteo Ravaioli, Alessia Perrucci, Annalisa Astolfi, Fabio Piscaglia and Laura Gramantieri
Cancers 2020, 12(9), 2674; https://doi.org/10.3390/cancers12092674 - 19 Sep 2020
Cited by 13 | Viewed by 2743
Abstract
Background and Aims: HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC. Methods: we investigated whether sofosbuvir and daclatasvir [...] Read more.
Background and Aims: HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC. Methods: we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results observed in HCC cell lines were validated in non-HCC cancer-derived cell lines and a preliminary series of human HCC tissues by qPCR and IHC. Results: DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects. Off-target gene modulation, mainly affecting ribosomal genes, mitochondrial functions and histones, points to epigenetics and proliferation as relevant events, consistent with matched phenotypic changes. A preliminary validation of in vitro findings was performed in a restricted cohort of HCC patients previously treated with DAAs, with immunohistochemical correlations suggesting DAA-treated HCCs to be more aggressive in terms of migration and epidermal-to-mesenchymal transition. Conclusions: Our findings suggested the possible occurrence of off-target effects ultimately modulating cell proliferation and/or migration and potentially justified previous findings showing some instances of particularly aggressive HCC recurrence as well as reduced incidence of recurrence of HCC following treatment with DAAs. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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19 pages, 3229 KiB  
Article
SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation
by Alexandra Elisabeth Wagner, Thomas Schwarzmayr, Beate Häberle, Christian Vokuhl, Irene Schmid, Markus Kaller, Heiko Hermeking, Dietrich von Schweinitz and Roland Kappler
Cancers 2020, 12(8), 2294; https://doi.org/10.3390/cancers12082294 - 15 Aug 2020
Cited by 13 | Viewed by 2907
Abstract
Hepatoblastoma (HB) is the most common malignant liver tumor in childhood and it generally has a good prognosis. However, if associated with aggressive metastatic disease, outcome is still poor. The molecular mechanisms leading to metastatic spread in HB patients are still unknown. By [...] Read more.
Hepatoblastoma (HB) is the most common malignant liver tumor in childhood and it generally has a good prognosis. However, if associated with aggressive metastatic disease, outcome is still poor. The molecular mechanisms leading to metastatic spread in HB patients are still unknown. By combining RNA-sequencing and a genome-wide methylome analysis, we identified the transcription factor SP8 and the growth factor FGF8 among the most strongly upregulated genes in metastatic HB cases, with a concomitant robust demethylation of the respective promoter regions. Of note, high expression of both candidates was associated with the aggressive C2 subtype of the 16-gene signature and poor survival. Chromatin immunoprecipitation revealed a direct transcriptional regulation of FGF8 through binding of SP8 to the FGF8 promoter. Gain- and loss-of-function experiments proved promoting effects of SP8 on motility, self-renewal, migration, and the invasive potential of HB cells. Moreover, stable overexpression of SP8 in Hep3B cells resulted in the acquisition of a mesenchymal phenotype and a strong upregulation of epithelial-mesenchymal transition-associated genes. Using KRAB-mediated CRISPR-dCas9 interference directed against FGF8, we could show that FGF8 is essential for the SP8-mediated aggressive tumor behavior. Treatment of HB cell lines with the pan SP family inhibitor mithramycin A resulted in a significant inhibition of their clonogenic growth. In summary, we identified SP8 and FGF8 as key players in aggressive traits of HB and propose SP8 inhibiting drugs as a new effective treatment strategy especially for metastatic tumors. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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16 pages, 1784 KiB  
Article
Optimizing Sequential Systemic Therapies for Advanced Hepatocellular Carcinoma: A Decision Analysis
by Giuseppe Cabibbo, Ciro Celsa, Marco Enea, Salvatore Battaglia, Giacomo Emanuele Maria Rizzo, Stefania Grimaudo, Domenica Matranga, Massimo Attanasio, Paolo Bruzzi, Antonio Craxì and Calogero Cammà
Cancers 2020, 12(8), 2132; https://doi.org/10.3390/cancers12082132 - 31 Jul 2020
Cited by 17 | Viewed by 4521
Abstract
Background: An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. Methods: A Markov model was built [...] Read more.
Background: An optimal sequential systemic therapy for advanced hepatocellular carcinoma (HCC) has not been discovered. We developed a decision model based on available clinical trials to identify an optimal risk/benefit strategy for sequences of novel systemic agents. Methods: A Markov model was built to simulate overall survival (OS) among patients with advanced HCC. Three first-line (single-agent Sorafenib or Lenvatinib, and combination of Atezolizumab plus Bevacizumab) followed by five second-line treatments (Regorafenib, Cabozantinib, Ramucirumab, Nivolumab, Pembrolizumab) were compared in fifteen sequential strategies. The likelihood of transition between states (initial treatment, cancer progression, death) was derived from clinical trials. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥grade 3) were calculated. The innovative measure, called incremental safety-effectiveness ratio (ISER), of the two best sequential treatments was calculated as the difference in probability of SAEs divided by LYG. Results: Lenvatinib followed by Nivolumab (median OS, 27 months) was the most effective sequence, producing a LYG of 0.75, while Atezolizumab plus Bevacizumab followed by Nivolumab was the safest sequence (SAEs 40%). Accordingly, the net health benefit assessed by ISER favored Lenvatinib followed by Nivolumab, compared to Atezolizumab plus Bevacizumab, followed by Nivolumab in 52% of cases. Conclusion: Further sequential clinical trials or large-scale real-world studies may prove useful to evaluate the net health benefit of the best sequential treatment for advanced HCC. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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30 pages, 3675 KiB  
Article
Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach
by Jesús M. Urman, José M. Herranz, Iker Uriarte, María Rullán, Daniel Oyón, Belén González, Ignacio Fernandez-Urién, Juan Carrascosa, Federico Bolado, Lucía Zabalza, María Arechederra, Gloria Alvarez-Sola, Leticia Colyn, María U. Latasa, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, María J. Iraburu, Marta Iruarrizaga-Lejarreta, Cristina Alonso, Bruno Sangro, Ana Purroy, Isabel Gil, Lorena Carmona, Francisco Javier Cubero, María L. Martínez-Chantar, Jesús M. Banales, Marta R. Romero, Rocio I.R. Macias, Maria J. Monte, Jose J. G. Marín, Juan J. Vila, Fernando J. Corrales, Carmen Berasain, Maite G. Fernández-Barrena and Matías A. Avilaadd Show full author list remove Hide full author list
Cancers 2020, 12(6), 1644; https://doi.org/10.3390/cancers12061644 - 21 Jun 2020
Cited by 36 | Viewed by 5593
Abstract
Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of [...] Read more.
Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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Review

Jump to: Research

22 pages, 4504 KiB  
Review
Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors
by Sofia Lachiondo-Ortega, Teresa Cardoso Delgado, Blanca Baños-Jaime, Alejandro Velázquez-Cruz, Irene Díaz-Moreno and María Luz Martínez-Chantar
Cancers 2022, 14(11), 2666; https://doi.org/10.3390/cancers14112666 - 27 May 2022
Cited by 7 | Viewed by 2843
Abstract
Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, [...] Read more.
Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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17 pages, 650 KiB  
Review
Current Advances in Basic and Translational Research of Cholangiocarcinoma
by Keisaku Sato, Leonardo Baiocchi, Lindsey Kennedy, Wenjun Zhang, Burcin Ekser, Shannon Glaser, Heather Francis and Gianfranco Alpini
Cancers 2021, 13(13), 3307; https://doi.org/10.3390/cancers13133307 - 01 Jul 2021
Cited by 6 | Viewed by 2863
Abstract
Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are [...] Read more.
Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are limited since early diagnosis is challenging, and the efficacy of chemotherapy or radiotherapy is also limited because CCA is a heterogeneous malignancy. Basic research is important for CCA to establish novel diagnostic testing and more effective therapies. Previous studies have introduced new techniques and methodologies for animal models, in vitro models, and biomarkers. Recent experimental strategies include patient-derived xenograft, syngeneic mouse models, and CCA organoids to mimic heterogeneous CCA characteristics of each patient or three-dimensional cellular architecture in vitro. Recent studies have identified various novel CCA biomarkers, especially non-coding RNAs that were associated with poor prognosis or metastases in CCA patients. This review summarizes current advances and limitations in basic and translational studies of CCA. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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22 pages, 2005 KiB  
Review
Biomarkers in Hepatobiliary Cancers: What Is Useful in Clinical Practice?
by Alice Boilève, Marc Hilmi, Matthieu Delaye, Annemilaï Tijeras-Raballand and Cindy Neuzillet
Cancers 2021, 13(11), 2708; https://doi.org/10.3390/cancers13112708 - 30 May 2021
Cited by 20 | Viewed by 3551
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment [...] Read more.
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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13 pages, 780 KiB  
Review
Current Status and Future Perspectives of Perioperative Therapy for Resectable Biliary Tract Cancer: A Multidisciplinary Review
by Changhoon Yoo, Sang Hyun Shin, Joon-Oh Park, Kyu-Pyo Kim, Jae Ho Jeong, Baek-Yeol Ryoo, Woohyung Lee, Ki-Byung Song, Dae-Wook Hwang, Jin-hong Park and Jae Hoon Lee
Cancers 2021, 13(7), 1647; https://doi.org/10.3390/cancers13071647 - 01 Apr 2021
Cited by 11 | Viewed by 4220
Abstract
Biliary tract cancers (BTCs) are a group of aggressive malignancies that arise from the bile duct and gallbladder. BTCs include intrahepatic cholangiocarcinoma (IH-CCA), extrahepatic cholangiocarcinoma (EH-CCA), and gallbladder cancer (GBCA). BTCs are highly heterogeneous cancers in terms of anatomical, clinical, and pathological characteristics. [...] Read more.
Biliary tract cancers (BTCs) are a group of aggressive malignancies that arise from the bile duct and gallbladder. BTCs include intrahepatic cholangiocarcinoma (IH-CCA), extrahepatic cholangiocarcinoma (EH-CCA), and gallbladder cancer (GBCA). BTCs are highly heterogeneous cancers in terms of anatomical, clinical, and pathological characteristics. Until recently, the treatment of resectable BTC, including surgery, adjuvant chemotherapy, and radiation therapy, has largely been based on institutional practice guidelines and evidence from small retrospective studies. Recently, several large randomized prospective trials have been published, and there are ongoing randomized trials for resectable BTC. In this article, we review prior and recently updated evidence regarding surgery, adjuvant and neoadjuvant chemotherapy, and adjuvant radiation therapy for patients with resectable BTC. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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18 pages, 739 KiB  
Review
Pathogenetic Role and Clinical Implications of Regulatory RNAs in Biliary Tract Cancer
by Nduka Ofoeyeno, Emmanuel Ekpenyong and Chiara Braconi
Cancers 2021, 13(1), 12; https://doi.org/10.3390/cancers13010012 - 22 Dec 2020
Cited by 10 | Viewed by 11644
Abstract
Biliary tract cancer (BTC) is characterised by poor prognosis and low overall survival in patients. This is generally due to minimal understanding of its pathogenesis, late diagnosis and limited therapeutics in preventing or treating BTC patients. Non-coding RNA (ncRNA) are small RNAs (mRNA) [...] Read more.
Biliary tract cancer (BTC) is characterised by poor prognosis and low overall survival in patients. This is generally due to minimal understanding of its pathogenesis, late diagnosis and limited therapeutics in preventing or treating BTC patients. Non-coding RNA (ncRNA) are small RNAs (mRNA) that are not translated to proteins. ncRNAs were considered to be of no importance in the genome, but recent studies have shown they play essential roles in biology and oncology such as transcriptional repression and degradation, thus regulating mRNA transcriptomes. This has led to investigations into the role of ncRNAs in the pathogenesis of BTC, and their clinical implications. In this review, the mechanisms of action of ncRNA are discussed and the role of microRNAs in BTC is summarised. The scope of this review will be limited to miRNA as they have been shown to play the most significant roles in BTC progression. There is huge potential in miRNA-based biomarkers and therapeutics in BTC, but more studies, research and technological advancements are required before it can be translated into clinical practice for patients. Full article
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
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