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Cancers
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Translational Research of Liver Cancer
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Translational Research of Liver Cancer

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 13009

Special Issue Editor

Prof. Dr. Farshid Dayyani

E-Mail Website
Guest Editor
Hematology Oncology, University of California, Irvine, CA 92868, USA
Interests: gastrointestinal cancers; hepatobiliary cancers; biomarkers; therapy development

Special Issue Information

Dear Colleagues,

The incidence of livers cancers has more than tripled over the past 30 years.

Significant progress has been made recently with regard to treatment options, and in addition to immunotherapies and anti-angiogenic agents, targeted therapies have been approved for specific molecular subsets.

The growing number of treatment options for primary livers cancers, i.e., mainly hepatocellular carcinomas and intrahepatic cholangiocarcinomas, requires novel advances in biomarker discovery, patient stratification, and treatment sequencing more than ever.

In this Special Edition, I would like to highlight cutting-edge translational work which might hopefully shed more light into the biology of primary liver cancers and also guide the necessary next steps in developing better treatment strategies for patients at all stages of liver cancer.

Your translational research has significantly contributed to the field beyond pure drug development, and I would like to invite you to share your work with other colleagues around the globe.

I look forward to your response.

Prof. Dr. Farshid Dayyani

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
  • biomarkers
  • treatment selection
  • tumor microenvironment
  • immunotherapy
  • precision medicine

Published Papers (6 papers)

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Research

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14 pages, 6790 KiB  
Article
Drug-Eluting Embolic Loaded with Tyrosine Kinase Inhibitor Targeted Therapies for Transarterial Chemoembolization in a VX2 Model
by Nadine Abi-Jaoudeh, Ben Sadeghi, Hanna Javan, Jim Na, Graham Beaton, Fabio Tucci, Satheesh Ravula and David K. Imagawa
Cancers 2023, 15(12), 3236; https://doi.org/10.3390/cancers15123236 - 18 Jun 2023
Cited by 1 | Viewed by 1367
Abstract
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, [...] Read more.
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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16 pages, 2691 KiB  
Article
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation
by Md Gulam Musawwir Khan, Nadia Boufaied, Mehdi Yeganeh, Rajani Kandhi, Stephanie Petkiewicz, Ankur Sharma, Akihiko Yoshimura, Gerardo Ferbeyre, David P. Labbé, Sheela Ramanathan and Subburaj Ilangumaran
Cancers 2023, 15(3), 905; https://doi.org/10.3390/cancers15030905 - 31 Jan 2023
Cited by 5 | Viewed by 2315
Abstract
SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic [...] Read more.
SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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20 pages, 3451 KiB  
Article
Trends in Liver Cancer Incidence and Survival in Italy by Histologic Type, 2003–2017
by Silvia Mancini, Lauro Bucchi, Federica Zamagni, Stefano Guzzinati, Luigino Dal Maso, Massimo Rugge, Lucia Bisceglia, Diego Serraino, Claudia Casella, Adele Caldarella, Fabio Falcini, Antonino Musolino, Giuliano Carrozzi, Roberto Vito Rizzello, Lucia Mangone, Guido Mazzoleni, Pietro Seghini, Stefano Ferretti and the Italian Cancer Registries’ Collaborative Group
Cancers 2022, 14(24), 6162; https://doi.org/10.3390/cancers14246162 - 14 Dec 2022
Cited by 1 | Viewed by 1529
Abstract
(1) Background: Liver cancer in Italy is characterised by one of the highest incidence rates worldwide outside of Asia coupled with comparatively favourable survival figures. The objective of this study was to evaluate the most recent epidemiologic trends of the disease. (2) Methods: [...] Read more.
(1) Background: Liver cancer in Italy is characterised by one of the highest incidence rates worldwide outside of Asia coupled with comparatively favourable survival figures. The objective of this study was to evaluate the most recent epidemiologic trends of the disease. (2) Methods: Thirteen cancer registries covering a population of about 12,740,000 (21% of the national population) made available the records of 35,574 cases registered between 2003 and 2017. Trends in age-standardised (Europe 2013) incidence rates were analysed using the results of age–drift models. Trends in survival were analysed using 1-year, 2-year, 5-year and 10-year net survival (NS) and 5|1-year and 5|2-year conditional NS. (3) Results: Over the study period, the average annual incidence rates per 100,000 persons were 29.4 (men) and 9.4 (women) for total liver cancer; 14.6 and 3.5 for hepatocellular carcinoma (HCC); 1.8 and 1.1 for intrahepatic cholangiocarcinoma (ICC); and 13.0 and 4.8 for the ‘other liver cancer types’ group. The incidence of total liver cancer and HCC decreased significantly for both sexes. For total liver cancer, the estimated average annual percent change was −1.6% among men and −2.1% among women. For HCC, the change was −1.3% among men and −2.7% among women. ICC followed an opposite trend. For men, the risk of HCC had two peaks, one in the birth cohorts of 1928 and 1933 and another, more moderate peak in the cohort of 1958. Men and women exhibited comparable improvements in both early and mid-term conditional NS from HCC. In 2013–2017, 5-year NS was 28.9% (95% CI: 27.3%; 30.6%) for men and 30.1% (95% CI: 26.9%; 33.5%) for women. The uptrend in survival from ICC was less pronounced and was weakly significant, with a 5-year NS in 2013-2017 of 13.9% (95% CI: 10.8%; 17.3%) for men and 17.4% (95% CI: 13.5%; 21.7%) for women. (4) Conclusions: The opposite incidence trends of HCC and ICC confirm a pattern observed in other populations. The generalised, albeit slow, improvement in survival from HCC indicates a trend towards earlier detection coupled with improvements in treatments. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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21 pages, 5914 KiB  
Article
Synergistic Effects of Sanglifehrin-Based Cyclophilin Inhibitor NV651 with Cisplatin in Hepatocellular Carcinoma
by Sonia Simón Serrano, Michele Tavecchio, Josef Mallik, Alvar Grönberg, Eskil Elmér, Chamseddine Kifagi, Philippe Gallay, Magnus Joakim Hansson and Ramin Massoumi
Cancers 2022, 14(19), 4553; https://doi.org/10.3390/cancers14194553 - 20 Sep 2022
Cited by 2 | Viewed by 1912
Abstract
Hepatocellular carcinoma (HCC), commonly diagnosed at an advanced stage, is the most common primary liver cancer. Owing to a lack of effective HCC treatments and the commonly acquired chemoresistance, novel therapies need to be investigated. Cyclophilins—intracellular proteins with peptidyl-prolyl isomerase activity—have been shown [...] Read more.
Hepatocellular carcinoma (HCC), commonly diagnosed at an advanced stage, is the most common primary liver cancer. Owing to a lack of effective HCC treatments and the commonly acquired chemoresistance, novel therapies need to be investigated. Cyclophilins—intracellular proteins with peptidyl-prolyl isomerase activity—have been shown to play a key role in therapy resistance and cell proliferation. Here, we aimed to evaluate changes in the gene expression of HCC cells caused by cyclophilin inhibition in order to explore suitable combination treatment approaches, including the use of chemoagents, such as cisplatin. Our results show that the novel cyclophilin inhibitor NV651 decreases the expression of genes involved in several pathways related to the cancer cell cycle and DNA repair. We evaluated the potential synergistic effect of NV651 in combination with other treatments used against HCC in cisplatin-sensitive cells. NV651 showed a synergistic effect in inhibiting cell proliferation, with a significant increase in intrinsic apoptosis in combination with the DNA crosslinking agent cisplatin. This combination also affected cell cycle progression and reduced the capacity of the cell to repair DNA in comparison with a single treatment with cisplatin. Based on these results, we believe that the combination of cisplatin and NV651 may provide a novel approach to HCC treatment. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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15 pages, 1803 KiB  
Article
Systemic Therapy Is Associated with Improved Oncologic Outcomes in Resectable Stage II/III Intrahepatic Cholangiocarcinoma: An Examination of the National Cancer Database over the Past Decade
by Rebecca Marcus, Wade Christopher, Jennifer Keller, Sean Nassoiy, Shu-Ching Chang, Melanie Goldfarb, Ronald Wolf and Zeljka Jutric
Cancers 2022, 14(17), 4320; https://doi.org/10.3390/cancers14174320 - 03 Sep 2022
Cited by 2 | Viewed by 1749
Abstract
Limited evidence-based management guidelines for resectable intrahepatic cholangiocarcinoma (ICC) currently exist. Using a large population-based cancer registry; the utilization rates and outcomes for patients with clinical stages I-III ICC treated with neoadjuvant chemotherapy (NAT) in relation to other treatment strategies were investigated, as [...] Read more.
Limited evidence-based management guidelines for resectable intrahepatic cholangiocarcinoma (ICC) currently exist. Using a large population-based cancer registry; the utilization rates and outcomes for patients with clinical stages I-III ICC treated with neoadjuvant chemotherapy (NAT) in relation to other treatment strategies were investigated, as were the predictors of treatment regimen utilization. Oncologic outcomes were compared between treatment strategies. Amongst 2736 patients, chemotherapy utilization was low; however, NAT use increased from 4.3% to 7.2% (p = 0.011) over the study period. A higher clinical stage was predictive of the use of NAT, while higher pathologic stage and margin-positive resections were predictive of the use of adjuvant therapy (AT). For patients with more advanced disease, the receipt of NAT or AT was associated with significantly improved survival compared to surgery alone (cStage II, p = 0.040; cStage III, p = 0.003). Furthermore, patients receiving NAT were more likely to undergo margin-negative resections compared to those treated with AT (72.5% vs. 62.6%, p = 0.027), despite having higher-risk tumors. This analysis of treatment strategies for resectable ICC suggests a benefit for systemic therapy. Prospective and randomized studies evaluating the sequencing of treatments for patients with high-risk resectable ICC are needed. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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Review

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19 pages, 1093 KiB  
Review
Optimizing the Diagnosis and Biomarker Testing for Patients with Intrahepatic Cholangiocarcinoma: A Multidisciplinary Approach
by May T. Cho, Sepideh Gholami, Dorina Gui, Sooraj L. Tejaswi, Ghaneh Fananapazir, Nadine Abi-Jaoudeh, Zeljka Jutric, Jason B. Samarasena, Xiaodong Li, Jennifer B. Valerin, Jacob Mercer and Farshid Dayyani
Cancers 2022, 14(2), 392; https://doi.org/10.3390/cancers14020392 - 13 Jan 2022
Cited by 9 | Viewed by 3272
Abstract
Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the [...] Read more.
Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review. Full article
(This article belongs to the Special Issue Translational Research of Liver Cancer)
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