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Cancers
Special Issues
Primary and Secondary Liver Tumors
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Primary and Secondary Liver Tumors

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 15684

Special Issue Editor

Prof. Dr. Claus Hellerbrand

E-Mail Website
Guest Editor
Institute of Biochemistry, Friedrich-Alexander University, Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany
Interests: hepatocellular cancer; hepatic metastasis; tumor metabolism; chemotherapy induced steatohepatitis

Special Issue Information

Dear Colleagues,

Primary liver cancer is one of the leading causes of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most frequent primary malignant hepatic tumor. Incidence and mortality rates of HCC have been increasing in recent years, and the identification of innovative therapeutic targets, as well as valid prognostic markers, is highly needed.

Moreover, the liver is a highly metastasis-permissive organ. The true prevalence of metastatic liver disease is unknown but, depending on the origin of the primary tumor, 30%–70% of patients dying of cancer have hepatic metastases, i.e., develop secondary liver tumors. Despite significant advances in the treatment of hepatic metastasis, they remain a critical determinant of patients’ survival.

The molecular and clinical features of primary versus secondary liver tumors are distinct, but these conditions also have overlapping pathways of oncogenesis; additionally, there are similarities regarding how nonparenchymal liver cells interact with malignantly transformed hepatocytes and extrahepatic tumor cells. The stromal reaction in cancer is similar to the reaction induced by chronic liver injury. Furthermore, it has to be noted that the liver constitutes a unique environment for cancer cells such as its unique immune regulatory functions or its nutrient rich blood supply via the portal vein. Still, the molecular mechanisms that render the liver so hospitable to cancer cells across different tumor types need to be further elucidated for the development of new prognostic markers and therapies.

This Special Issue welcomes both original papers and review articles addressing the mechanisms driving the development and progression of primary and secondary liver tumors.

Prof. Claus Hellerbrand
Guest Editor

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 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
  • cholangiocellular carcinoma
  • hepatic metastasis
  • secondary liver cancer
  • stromal reaction

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Published Papers (5 papers)

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Research

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16 pages, 1695 KiB  
Article
Early Detection of Local Tumor Progression after Irreversible Electroporation (IRE) of Hepatocellular Carcinoma Using Gd-EOB-DTPA-Based MR Imaging at 3T
by Wolf Bäumler, Philipp Wiggermann, Lukas Lürken, Marco Dollinger, Christian Stroszczynski, Lukas P. Beyer and Andreas Schicho
Cancers 2021, 13(7), 1595; https://doi.org/10.3390/cancers13071595 - 30 Mar 2021
Cited by 2 | Viewed by 1924
Abstract
This single-center retrospective study was conducted to improve the early detection of local tumor progression (LTP) after irreversible electroporation (IRE) of a hepatocellular carcinoma (HCC) using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-based 3T MR imaging and to identify helpful signal characteristics by comparing [...] Read more.
This single-center retrospective study was conducted to improve the early detection of local tumor progression (LTP) after irreversible electroporation (IRE) of a hepatocellular carcinoma (HCC) using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-based 3T MR imaging and to identify helpful signal characteristics by comparing 23 patients with and 60 patients without LTP. To identify the differences in the sensitivity of MRI sequences, the specificity, positive prediction value, negative prediction value (NPV) and diagnostic odds ratio were calculated. A chi-squared test, two-tailed student’s t-test and binary logistic regression model were used to detect distinct patient characteristics and variables for the prediction of LTP. LTP was mostly detected in the peripheral ablation zone (82.6%) within the first six months (87.0%). The central LTP ablation area presented more hypointensities in T1 p.v. (sensitivity: 95.0%; NPV: 90.0%) and in T1 d.p. (sensitivity: 100.0%; NPV: 100.0) while its peripheral part showed more hyperintensities in T2 BLADE (sensitivity: 95.5%; NPV: 80.0%) and in diffusion sequences (sensitivity: 90.0%). Liver cirrhosis seems to be an unfavorable prognosticator for LTP (p = 0.039). In conclusion, LTP mostly occurs in the peripheral ablation zone within six months after IRE. Despite often exhibiting atypical Gd-EOB-DTPA MR signal characteristics, T2 BLADE and diffusion sequences were helpful for their detection in the peripheral zone while T1 p.v. and T1 d.p. had the highest sensitivity in the central zone. Full article
(This article belongs to the Special Issue Primary and Secondary Liver Tumors)
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13 pages, 2779 KiB  
Article
Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma
by Valerie Fritz, Lara Malek, Anne Gaza, Laura Wormser, Majken Appel, Andreas E. Kremer, Wolfgang E. Thasler, Jürgen Siebler, Markus F. Neurath, Claus Hellerbrand, Anja K. Bosserhoff and Peter Dietrich
Cancers 2021, 13(5), 1183; https://doi.org/10.3390/cancers13051183 - 9 Mar 2021
Cited by 5 | Viewed by 2364
Abstract
Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control [...] Read more.
Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer. Full article
(This article belongs to the Special Issue Primary and Secondary Liver Tumors)
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12 pages, 2036 KiB  
Article
Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells
by Tatjana Seitz, Christina Hackl, Kim Freese, Peter Dietrich, Abdo Mahli, Reinhard Manfred Thasler, Wolfgang Erwin Thasler, Sven Arke Lang, Anja Katrin Bosserhoff and Claus Hellerbrand
Cancers 2021, 13(3), 511; https://doi.org/10.3390/cancers13030511 - 29 Jan 2021
Cited by 20 | Viewed by 2801
Abstract
Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of [...] Read more.
Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis. Full article
(This article belongs to the Special Issue Primary and Secondary Liver Tumors)
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22 pages, 5697 KiB  
Article
C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation
by Celia Sequera, Paloma Bragado, Sara Manzano, Maria Arechederra, Sylvie Richelme, Alvaro Gutiérrez-Uzquiza, Aránzazu Sánchez, Flavio Maina, Carmen Guerrero and Almudena Porras
Cancers 2020, 12(8), 2282; https://doi.org/10.3390/cancers12082282 - 14 Aug 2020
Cited by 7 | Viewed by 3186
Abstract
The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and [...] Read more.
The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors. Full article
(This article belongs to the Special Issue Primary and Secondary Liver Tumors)
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Review

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15 pages, 1051 KiB  
Review
Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease
by María Arechederra, Miriam Recalde, María Gárate-Rascón, Maite G. Fernández-Barrena, Matías A. Ávila and Carmen Berasain
Cancers 2021, 13(6), 1265; https://doi.org/10.3390/cancers13061265 - 12 Mar 2021
Cited by 22 | Viewed by 4229
Abstract
Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, [...] Read more.
Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment. Full article
(This article belongs to the Special Issue Primary and Secondary Liver Tumors)
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