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17 pages, 2777 KiB

Open AccessArticle

A Critical Role of the IL-22–IL-22 Binding Protein Axis in Hepatocellular Carcinoma

by Anastasios D. Giannou, Jöran Lücke, Dörte Kleinschmidt, Ahmad Mustafa Shiri, Babett Steglich, Mikolaj Nawrocki, Tao Zhang, Dimitra E. Zazara, Jan Kempski, Lilan Zhao, Olympia Giannou, Theodora Agalioti, Leonie Brockmann, Franziska Bertram, Morsal Sabihi, Marius Böttcher, Florian Ewald, Kornelius Schulze, Johann von Felden, Andres Machicote, Ioannis C. Maroulis, Petra C. Arck, Julia-Kristin Graß, Baris Mercanoglu, Matthias Reeh, Stefan Wolter, Michael Tachezy, Hannes Seese, Myrto Theodorakopoulou, Panagis M. Lykoudis, Asmus Heumann, Faik G. Uzunoglu, Tarik Ghadban, Oliver Mann, Jakob R. Izbicki, Jun Li, Anna Duprée, Nathaniel Melling, Nicola Gagliani and Samuel Huber Show full author list Hide full author list

Cancers 2022, 14(24), 6019; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246019 - 07 Dec 2022

Cited by 4 | Viewed by 2126

Abstract

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a [...] Read more.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4⁺ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1^flox/flox × Alb^Cre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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16 pages, 3408 KiB

Open AccessArticle

Limitations of Nerve Fiber Density as a Prognostic Marker in Predicting Oncological Outcomes in Hepatocellular Carcinoma

by Jan Bednarsch, Xiuxiang Tan, Zoltan Czigany, Georg Wiltberger, Roman David Buelow, Peter Boor, Sven Arke Lang, Tom Florian Ulmer, Ulf Peter Neumann and Lara Rosaline Heij

Cancers 2022, 14(9), 2237; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092237 - 29 Apr 2022

Cited by 2 | Viewed by 1639

Abstract

It has been shown that the presence and density of nerve fibers (NFs; NFD) in the tumor microenvironment (TME) may play an important prognostic role in predicting long-term oncological outcomes in various malignancies. However, the role of NFD in the prognosis of hepatocellular [...] Read more.

It has been shown that the presence and density of nerve fibers (NFs; NFD) in the tumor microenvironment (TME) may play an important prognostic role in predicting long-term oncological outcomes in various malignancies. However, the role of NFD in the prognosis of hepatocellular carcinoma (HCC) is yet to be explored. To this end, we aimed to investigate the impact of NFs on oncological outcomes in a large European single-center cohort of HCC patients. In total, 153 HCC patients who underwent partial hepatectomy in a curative-intent setting between 2010 and 2021 at our university hospital were included in this study. Group comparisons between patients with and without NFs were conducted and the association of recurrence-free survival (RFS) and overall survival (OS) with the presence of NFs and other clinico-pathological variables were determined by univariate and multivariable Cox regression models. Patients with NFs in the TME presented with a median OS of 66 months (95% CI: 30–102) compared to 42 months (95% CI: 20–63) for patients without NFs (p = 0.804 log-rank). Further, RFS was 26 months (95% CI: 12–40) for patients with NFs compared to 18 months (95% CI: 9–27) for patients without NFs (p = 0.666 log-rank). In a subgroup analysis, patients with NFD ≤ 5 showed a median OS of 54 months (95% CI: 11–97) compared to 48 months (95% CI: 0–106) for the group of patients with NFD > 5 (p = 0.787 log-rank). Correspondingly, the RFS was 26 months (95% CI: 10–42) in patients with NFD ≤ 5 and 29 months (95% CI: 14–44) for the subcohort with NFD > 5 (p = 0.421 log-rank). Further, group comparisons showed no clinico-pathological differences between patients with NFs (n = 76) and without NFs (n = 77) and NFs were not associated with OS (p = 0.806) and RFS (p = 0.322) in our Cox regression models. In contrast to observations in various malignancies, NFs in the TME and NFD are not associated with long-term oncological outcomes in HCC patients undergoing surgery. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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22 pages, 12258 KiB

Open AccessArticle

Combined Targeting of AKT and mTOR Inhibits Tumor Formation of EpCAM⁺ and CD90⁺ Human Hepatocellular Carcinoma Cells in an Orthotopic Mouse Model

by Mohamed Moustafa, Katarzyna-Krystyna Dähling, Armin Günther, Leonie Riebandt, Daniel J. Smit, Kristoffer Riecken, Carina Schröder, Ruimeng Zhuang, Till Krech, Malte Kriegs, Boris Fehse, Jakob R. Izbicki, Lutz Fischer, Björn Nashan, Jun Li and Manfred Jücker

Cancers 2022, 14(8), 1882; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081882 - 08 Apr 2022

Cited by 5 | Viewed by 2437

Abstract

The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In [...] Read more.

The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In this study, we demonstrate that combined treatment with AKT and mTOR inhibitors—i.e., MK2206 and RAD001—results in a synergistic reduction in proliferation of EpCAM⁺ and CD90⁺ HCC cells cultured either as adherent cells or as tumoroids in vitro. In addition, tumor growth was reduced by combined treatment with AKT and mTOR inhibitors in an orthotopic xenograft mouse model of an EpCAM⁺ HCC cell line (Huh7) and primary patient-derived EpCAM⁺ HCC cells (HCC1) as well as a CD90⁺ HCC-related cell line (SK-HEP1) in vivo. However, during AKT/mTOR treatment, outgrowth of therapy-resistant tumors was observed in all mice analyzed within a few weeks. Resistance was associated in most cases with restoration of AKT signaling in the tumors, intrahepatic metastases and distant metastases. In addition, an upregulation of the p38 MAPK pathway was identified in the AKT/mTOR inhibitor-resistant tumor cells by kinome profiling. The development of resistant cells during AKT/mTOR therapy was further analyzed by red-green-blue (RGB) marking of HCC cells, which revealed an outgrowth of a large number of Huh7 cells over a period of 6 months. In summary, our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of EpCAM⁺ as well as CD90⁺ HCC cells in vitro. However, the fast development of large numbers of resistant clones under AKT/mTOR therapy observed in vitro and in the orthotopic xenotransplantation mouse model in vivo strongly suggests that this therapy alone will not be sufficient to eliminate EpCAM⁺ or CD90⁺ cancer stem cells from HCC patients. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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13 pages, 1109 KiB

Open AccessArticle

Impact of Positive Radial Margin on Recurrence and Survival in Perihilar Cholangiocarcinoma

by Francesco Enrico D’Amico, Claudia Mescoli, Silvia Caregari, Alessio Pasquale, Ilaria Billato, Remo Alessandris, Jacopo Lanari, Domenico Bassi, Riccardo Boetto, Francesco D’Amico, Alessandro Vitale, Sara Lonardi, Enrico Gringeri and Umberto Cillo

Cancers 2022, 14(7), 1680; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071680 - 25 Mar 2022

Cited by 5 | Viewed by 1698

Abstract

In resected perihilar cholangiocarcinoma (PHC), positive ductal margin (DM) is associated with poor survival. There is currently little knowledge about the impact of positive radial margin (RM) when DM is negative. The aim of this study was to evaluate the incidence and the [...] Read more.

In resected perihilar cholangiocarcinoma (PHC), positive ductal margin (DM) is associated with poor survival. There is currently little knowledge about the impact of positive radial margin (RM) when DM is negative. The aim of this study was to evaluate the incidence and the role of positive RM. Patients who underwent surgery between 2005 and 2017 where retrospectively reviewed and stratified according to margin positivity: an isolated RM-positive group and DM ± RM group. Of the 75 patients identified; 34 (45.3%) had R1 resection and 17 had positive RM alone. Survival was poorer in patients with R1 resection compared to R0 (p = 0.019). After stratification according to margin positivity; R0 patients showed better survival than DM ± RM-positive patients (p = 0.004; MST 43.9 vs. 23.6 months), but comparable to RM-positive patients (p = 0.361; MST 43.9 vs. 39.5 months). Recurrence was higher in DM ± RM group compared to R0 (p = 0.0017; median disease-free survival (DFS) 15 vs. 30 months); but comparable between RM and R0 group (p = 0.39; DFS 20 vs. 30 months). In univariate and multivariate analysis, DM positivity resulted as a negative prognostic factor both for survival and recurrence. In conclusion, positive RM resections appear to have different recurrence patterns and survival rates than positive DM resections. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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16 pages, 13127 KiB

Open AccessArticle

Equal Efficacy and Safety Profile in Elderly Patients with Hepatocellular Carcinoma Receiving Palliative Treatment

by Thorben W. Fründt, Christian Casar, Johann von Felden, Ulrike Schöler, Maximilian Priebe, Jenny Kraczyk, Hannes Ahrend, Johannes Salamon, Gerhard Adam, Samuel Huber, Ansgar W. Lohse, Henning Wege and Kornelius Schulze

Cancers 2022, 14(3), 768; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030768 - 01 Feb 2022

Cited by 1 | Viewed by 1562

Abstract

Palliative treatment of elderly patients with hepatocellular carcinoma (HCC) is often challenging due to comorbidities or frailty, and data about the outcome and overall survival (OS) in these patients are limited. This was a retrospective single centre study. Patients were grouped according to [...] Read more.

Palliative treatment of elderly patients with hepatocellular carcinoma (HCC) is often challenging due to comorbidities or frailty, and data about the outcome and overall survival (OS) in these patients are limited. This was a retrospective single centre study. Patients were grouped according to their age as young (<60 years; YP), intermediate (60–70 years; IP) or elderly (>70 years; EP). Administration of chemotherapy or transarterial chemoembolization (TACE) was defined as palliative treatment. Therapy-related adverse events (AE) were assessed via CTCAE 5.0. Out of 656 patients analyzed, n = 359 received palliative treatment: YP: n = 90; IP: n = 127 and EP: n = 142. The median OS (months) in patients receiving TACE (n = 254) was 17 vs. 18 vs. 20 months for YP, IP, and EP, respectively (p = 0.44) and 15 vs. 16 vs. 17 months (p = 0.56), respectively, in patients receiving chemotherapy (n = 105). AEs differed non-significantly between the subgroups. Multivariate analysis revealed impaired liver function and advanced tumor stage as significant factors for impaired OS. In this study, the mOS and rate of AEs were equal between elderly and younger HCC patients receiving palliative treatment. Therefore, we propose regular palliative treatment stratification in spite of the high age of patients. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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17 pages, 1734 KiB

Open AccessArticle

Diagnostic and Prognostic Value of miR-16, miR-146a, miR-192 and miR-221 in Exosomes of Hepatocellular Carcinoma and Liver Cirrhosis Patients

by Thorben Fründt, Linda Krause, Elaine Hussey, Bettina Steinbach, Daniel Köhler, Johann von Felden, Kornelius Schulze, Ansgar W. Lohse, Henning Wege and Heidi Schwarzenbach

Cancers 2021, 13(10), 2484; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102484 - 19 May 2021

Cited by 23 | Viewed by 2455

Abstract

We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based [...] Read more.

We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based microarray cards containing 45 different miRNAs (training cohort). Then, four deregulated miRNAs (miR-16, miR-146a, miR-192, and miR-221) were quantified in the validation analysis using exosomes derived from 85 HCC patients, 50 liver cirrhosis patients, and 20 healthy individuals. Exosomal miR-146a (p = 0.0001), miR-192 (p = 0.002) and miR-221 (p = 0.032) were upregulated only in HCC patients. Repeated 10-fold cross validation showed that miR-146a differentiated HCC from liver cirrhosis patients with AUC of 0.80 ± 0.14 (sensitivity: 81 ± 13%, specificity: 58 ± 22%) in a logistic regression model. High miR-192 presence is associated with poor overall survival (OS) in all HCC patients (p = 0.027) and was predictor of OS in HCC patients in an uni- and multivariate Cox regression model. Moreover, decreased miR-16 levels correlated with OS in liver cirrhosis patients (p = 0.034). Our results emphasized that exosomes secreted into the plasma carry differentially expressed miRNAs of which in particular, miR-192, miR-146, and miR-16 are promising diagnostic and prognostic markers for both HCC and liver cirrhosis patients. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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Review

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20 pages, 733 KiB

Open AccessReview

Treatment of Intrahepatic Cholangiocarcinoma—A Multidisciplinary Approach

by Felix Krenzien, Nora Nevermann, Alina Krombholz, Christian Benzing, Philipp Haber, Uli Fehrenbach, Georg Lurje, Uwe Pelzer, Johann Pratschke, Moritz Schmelzle and Wenzel Schöning

Cancers 2022, 14(2), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020362 - 12 Jan 2022

Cited by 29 | Viewed by 8290

Abstract

Intrahepatic cholangiocarcinoma (iCC) is distinguished as an entity from perihilar and distal cholangiocarcinoma and gallbladder carcinoma. Recently, molecular profiling and histopathological features have allowed further classification. Due to the frequent delay in diagnosis, the prognosis for iCC remains poor despite major technical advances [...] Read more.

Intrahepatic cholangiocarcinoma (iCC) is distinguished as an entity from perihilar and distal cholangiocarcinoma and gallbladder carcinoma. Recently, molecular profiling and histopathological features have allowed further classification. Due to the frequent delay in diagnosis, the prognosis for iCC remains poor despite major technical advances and multimodal therapeutic approaches. Liver resection represents the therapeutic backbone and only curative treatment option, with the functional residual capacity of the liver and oncologic radicality being deciding factors for postoperative and long-term oncological outcome. Furthermore, in selected cases and depending on national guidelines, liver transplantation may be a therapeutic option. Given the often advanced tumor stage at diagnosis or the potential for postoperative recurrence, locoregional therapies have become increasingly important. These strategies range from radiofrequency ablation to transarterial chemoembolization to selective internal radiation therapy and can be used in combination with liver resection. In addition, adjuvant and neoadjuvant chemotherapies as well as targeted therapies and immunotherapies based on molecular profiles can be applied. This review discusses multimodal treatment strategies for iCC and their differential use. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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18 pages, 295 KiB

Open AccessReview

Robotic-Assisted Surgery for Primary Hepatobiliary Tumors—Possibilities and Limitations

by Julia Spiegelberg, Tanja Iken, Markus K. Diener and Stefan Fichtner-Feigl

Cancers 2022, 14(2), 265; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020265 - 06 Jan 2022

Cited by 9 | Viewed by 1993

Abstract

Hepatocellular and cholangiocellular carcinoma are fatal primary hepatic tumors demanding extensive liver resection. Liver surgery is technically challenging due to the complex liver anatomy, with an intensive and variant vascular and biliary system. Therefore, major hepatectomies in particular are often performed by open [...] Read more.

Hepatocellular and cholangiocellular carcinoma are fatal primary hepatic tumors demanding extensive liver resection. Liver surgery is technically challenging due to the complex liver anatomy, with an intensive and variant vascular and biliary system. Therefore, major hepatectomies in particular are often performed by open resection and minor hepatectomies are often performed minimally invasively. More centers have adopted robotic-assisted surgery, intending to improve the laparoscopic surgical limits, as it offers some technical benefits such as seven degrees of freedom and 3D visualization. The da Vinci^® Surgical System has dominated the surgical robot market since 2000 and has shown surgical feasibility, but there is still much controversy about its economic benefits and real benefits for the patient over the gold standard. The currently available retrospective case studies are difficult to compare, and larger, prospective studies and randomized trials are still urgently missing. Therefore, here we summarize the technical, surgical, and economic outcomes of robotic versus open and laparoscopic hepatectomies for primary liver tumors found in the latest literature reviews and meta-analyses. We conclude that complex robotic liver resections (RLR) are safe and feasible after the steep learning curve of the surgical team has plateaued. The financial burden is lower in high volume centers and is expected to decrease soon as new surgical systems will enter the market. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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