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New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity
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New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 19724

Special Issue Editors

Prof. Dr. Eugenio Gaudio

E-Mail Website
Guest Editor
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, I-00161 Rome, Italy
Interests: liver structure and ultrastructure; experimental and clinical hepatology and microcirculation; cholangiocytic cells; stem cells
Dr. Diletta Overi

E-Mail Website
Guest Editor
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
Interests: morphology of liver and biliary tree; stem/progenitor cell niches; cholangiopathies; cholangiocarcinoma
Dr. Vincenzo Cardinale

E-Mail Website
Guest Editor
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00161 Rome, Italy
Interests: diseases of the liver and biliary tree; cholangiopathies; cholangiocarcinoma

Special Issue Information

Dear Colleagues,

Cholangiocarcinoma is a rare cancer, but its incidence and mortality are constantly increasing. Cholangiocarcinoma is often diagnosed in advanced stages, thus compromising therapeutic options and resulting in a poor prognosis. This tumour can arise at any point of the biliary tree and has been divided into three subtypes: intrahepatic, perihilar, and distal cholangiocarcinoma. The anatomical location of cholangiocarcinoma implies a high heterogeneity in terms of morphology, cell of origin, and molecular subtyping, which has complicated the histologic and molecular classification of these tumours. Of note, cholangiocarcinoma is a desmoplastic tumour and is strongly influenced in its growth by interactions with highly variable stromal cell subpopulations and extracellular matrix components.

From a clinical point of view, cholangiocarcinoma’s heterogeneity hampered the definition of risk factors and early diagnosis, thus suggesting the need for personalized approaches to fully characterize the pathogenetic profiles of this cancer, with the aim of developing novel diagnostic tools and therapeutic targets.

The scope of this Special Issue is to provide recent advances in the field of cholangiocarcinoma, including morphologic classification, the definition of molecular profiles, the molecular interactions at the basis of biliary carcinogenesis, and the characterization of cell of origin, cancer stem cells, and tumour microenvironment. We welcome both review articles and original manuscripts that embrace novelty in tumour cell biology and differentiation.

Dr. Eugenio Gaudio
Dr. Diletta Overi
Dr. Vincenzo Cardinale
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. Cells 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 2700 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

  • liver
  • cholangiocyte
  • tumour
  • biliary tree
  • stroma
  • cancer-associated fibroblast
  • cancer stem cell
  • cell of origin

Published Papers (9 papers)

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Research

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24 pages, 4720 KiB  
Article
Galanin System in the Human Bile Duct and Perihilar Cholangiocarcinoma
by Sara Huber, Theresia Fitzner, René G. Feichtinger, Sarah Hochmann, Theo Kraus, Karl Sotlar, Barbara Kofler and Martin Varga
Cells 2023, 12(13), 1678; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12131678 - 21 Jun 2023
Viewed by 1326
Abstract
Background: Perihilar cholangiocarcinoma (pCCA) is characterised by poor outcomes. Early diagnosis is essential for patient survival. The peptide galanin (GAL) and its receptors GAL1–3 are expressed in various tumours. Detailed characterisation of the GAL system in pCCA is lacking. Our study sought [...] Read more.
Background: Perihilar cholangiocarcinoma (pCCA) is characterised by poor outcomes. Early diagnosis is essential for patient survival. The peptide galanin (GAL) and its receptors GAL1–3 are expressed in various tumours. Detailed characterisation of the GAL system in pCCA is lacking. Our study sought to characterise GAL and GAL1–3 receptor (GAL1–3–R) expression in the healthy human bile duct, in cholestasis and pCCA. Methods: Immunohistochemical staining was performed in healthy controls (n = 5) and in the peritumoural tissues (with and without cholestasis) (n = 20) and tumour tissues of pCCA patients (n = 33) using validated antibodies. The score values of GAL and GAL1–3–R expression were calculated and statistically evaluated. Results: GAL and GAL1–R were expressed in various bile duct cell types. GAL2–R was only slightly but still expressed in almost all the examined tissues, and GAL3–R specifically in cholangiocytes and capillaries. In a small pCCA patient cohort (n = 18), high GAL expression correlated with good survival, whereas high GAL3–R correlated with poor survival. Conclusions: Our in-depth characterisation of the GAL system in the healthy human biliary duct and pCCA in a small patient cohort revealed that GAL and GAL3–R expression in tumour cells of pCCA patients could potentially represent suitable biomarkers for survival. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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8 pages, 2358 KiB  
Communication
Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features
by Martin Cornillet, Helen Zemack, Hannes Jansson, Ernesto Sparrelid, Ewa Ellis and Niklas K. Björkström
Cells 2023, 12(12), 1663; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12121663 - 19 Jun 2023
Cited by 2 | Viewed by 1434
Abstract
Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had [...] Read more.
Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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12 pages, 2024 KiB  
Article
Expression of Checkpoint Molecules in the Tumor Microenvironment of Intrahepatic Cholangiocarcinoma: Implications for Immune Checkpoint Blockade Therapy
by Lara Heij, Jan Bednarsch, Xiuxiang Tan, Mika Rosin, Simone Appinger, Konrad Reichel, Dana Pecina, Michail Doukas, Ronald M. van Dam, Juan Garcia Vallejo, Florian Ulmer, Sven Lang, Tom Luedde, Flavio G. Rocha, Shivan Sivakumar and Ulf Peter Neumann
Cells 2023, 12(6), 851; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12060851 - 9 Mar 2023
Cited by 4 | Viewed by 2935
Abstract
Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, [...] Read more.
Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results: ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface (p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface (p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 (p = 0.048) and CD4_ICOS_TIGIT (p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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12 pages, 3899 KiB  
Article
The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth
by Kishor Pant, Seth Richard, Estanislao Peixoto, Jun Yin, Davis M. Seelig, Pietro Carotenuto, Massimiliano Salati, Brunella Franco, Lewis R. Roberts and Sergio A. Gradilone
Cells 2023, 12(5), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12050775 - 28 Feb 2023
Cited by 1 | Viewed by 2524
Abstract
It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research [...] Read more.
It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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Review

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13 pages, 1363 KiB  
Review
Relevance of Bile Acids in Cholangiocarcinoma Pathogenesis: Critical Revision and Future Directions
by Valentina Cossiga, Maria Guarino, Mario Capasso and Filomena Morisco
Cells 2023, 12(12), 1576; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12121576 - 7 Jun 2023
Viewed by 1579
Abstract
Cholangiocarcinoma (CCA), a highly heterogeneous cancer, is the second most common type of primary liver cancer. It is characterized by resistance to therapy and poor prognosis, with a 5-year survival rate lower than 20%. The pathogenesis of CCA is complex and multifactorial, and [...] Read more.
Cholangiocarcinoma (CCA), a highly heterogeneous cancer, is the second most common type of primary liver cancer. It is characterized by resistance to therapy and poor prognosis, with a 5-year survival rate lower than 20%. The pathogenesis of CCA is complex and multifactorial, and in recent years, bile acids (BAs) have been implicated in CCA development and prognosis. BAs belong to a category of amphipathic compounds that hold significant importance as signaling molecules and inflammatory agents. They possess the ability to activate transcriptional factors and cellular signaling pathways, thereby governing the regulation of lipid, glucose, and energy metabolism in diverse human disorders. These disorders encompass chronic liver diseases among other conditions. In this review, we provided an update on the current knowledge on the molecular mechanisms involving BAs in cholangiocarcinogenesis. Additionally, we analyzed the role of gut and biliary microbiota in CCA pathogenesis. Future research is required to better understand how to modulate BA activity and, possibly, identify new therapeutic strategies. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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14 pages, 294 KiB  
Review
Mutational Landscape of Cholangiocarcinoma According to Different Etiologies: A Review
by Simona Tavolari and Giovanni Brandi
Cells 2023, 12(9), 1216; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12091216 - 22 Apr 2023
Cited by 6 | Viewed by 1854
Abstract
Recent next-generation sequencing (NGS) studies on large cohorts of cholangiocarcinoma (CCA) patients have clearly revealed the extreme intra- and inter-tumoral molecular heterogeneity that characterizes this malignancy. The lack of a stereotyped molecular signature in CCA makes the identification of actionable therapeutic targets challenging, [...] Read more.
Recent next-generation sequencing (NGS) studies on large cohorts of cholangiocarcinoma (CCA) patients have clearly revealed the extreme intra- and inter-tumoral molecular heterogeneity that characterizes this malignancy. The lack of a stereotyped molecular signature in CCA makes the identification of actionable therapeutic targets challenging, making it mandatory to have a better understanding of the origin of such heterogeneity in order to improve the clinical outcome of these patients. Compelling evidence has shown that the CCA genomic landscape significantly differs according to anatomical subtypes and the underlying etiology, highlighting the importance of conducting molecular studies in different populations of CCA patients. Currently, some risk factors have been recognized in CCA development, while others are emerging from recent epidemiological studies. Nevertheless, the role of each etiologic factor in driving CCA genetic heterogeneity still remains unclear, and available studies are limited. In an attempt to shed more light on this issue, here we review the current literature data on the mutational spectrum of this disease according to different etiologies. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
15 pages, 1151 KiB  
Review
Impact of Aberrant β-Catenin Pathway on Cholangiocarcinoma Heterogeneity
by Elisa Lozano, Paula Sanchon-Sanchez, Ana Morente-Carrasco, Luis Miguel Chinchilla-Tábora, José L. Mauriz, Paula Fernández-Palanca, Jose J. G. Marin and Rocio I. R. Macias
Cells 2023, 12(8), 1141; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12081141 - 12 Apr 2023
Cited by 4 | Viewed by 2201
Abstract
The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not [...] Read more.
The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/β-catenin pathway plays a pivotal role. Alteration of β-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/β-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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27 pages, 1987 KiB  
Review
Heterogeneity of Cholangiocarcinoma Immune Biology
by Francesca Vita, Irene Olaizola, Francesco Amato, Colin Rae, Sergi Marco, Jesus M. Banales and Chiara Braconi
Cells 2023, 12(6), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12060846 - 8 Mar 2023
Cited by 7 | Viewed by 2564
Abstract
Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression [...] Read more.
Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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Other

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16 pages, 1166 KiB  
Systematic Review
Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis
by Giorgio Frega, Fernando P. Cossio, Jesus M. Banales, Vincenzo Cardinale, Rocio I. R. Macias, Chiara Braconi and Angela Lamarca
Cells 2023, 12(16), 2098; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12162098 - 19 Aug 2023
Cited by 8 | Viewed by 2179
Abstract
Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic [...] Read more.
Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. Methods: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. Results: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs—15 studies), perihilar–distal CCAs (p/dCCAs—7 studies), and gallbladder cancer (GBC—5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. Conclusion: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies. Full article
(This article belongs to the Special Issue New Insight on Cholangiocarcinoma and Pathogenetic Basis of Tumour Heterogeneity)
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