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Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma

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

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 69607

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Special Issue Editors

Prof. Dr. Pietro Invernizzi

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Guest Editor

Division of Gastroenterology, San Gerardo Hospital, University of Milano-Bicocca School of Medicine, 20900 Monza, Italy
Interests: gastroenterology; inflammatory bowel diseases; hepatology; neuroendocrine tumors
Special Issues, Collections and Topics in MDPI journals

Dr. Chiara Raggi

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Dip. Medicina Sperimentale e Clinica , Universita' di Firenze,Largo Brambilla 3, 50141 Firenze, Italy
Interests: cholangiocarcinoma; tumor stem-like cells; tumor stroma; tumor metabolism

Special Issue Information

Dear Colleagues,

Cholangiocarcinoma (CCA) is a rare and often fatal cancer that includes a heterogeneous group of liver tumors, originating from neoplastic proliferation of epithelial cells lining the bile ducts (colangiocytes), in the extrahepatic or intrahepatic segments. CCA represents the second most common primary liver cancer, after hepatocellular carcinoma. The incidence and mortality rates of CCA are increasing worldwide, and there is no effective treatment for the advanced forms of this tumor. Indeed, prognosis is poor, with a 5-year survival rate that is lower than 20%.

Resistance to current therapeutic strategies, a typical feature of cholangiocarcinoma, prevents the efficacy of conventional chemotherapeutic agents used to treat this form. Owing to the highly aggressive nature of CCA, late diagnosis, and lack of sensitivity to chemotherapeutic drugs, CCA remains a devastating disease.

To reduce global mortality from cholangiocarcinoma, efforts must be multifaceted and focus on prevention, early identification of high-risk individuals, and prompt diagnosis, as well as molecular-based targeted therapies for established disease. Therefore, understanding the genetic predisposition to CCA, the malignant properties of chemicals and environmental factors, the histopathological alterations occurring along CCA development and progression, the identification of diagnostic and prognostic markers, and the oncogenic potential of aberrantly activated or inactivated signaling pathways is extremely critical.

New studies will be tremendously helpful to addressing pivotal unsolved questions, such as intratumor heterogeneity, functional interplay between CCA cells and the tumor microenvironment, the role of signaling pathways crosstalk, metabolic addiction, and response/resistance to conventional and tailored therapies.

Given the importance of CCA in the field of medicine and research, Cells is launching this Special Issue to pinpoint the identification of novel therapeutic targets and thus inhibit CCA progression.

Prof. Pietro Invernizzi
Dr. Chiara Raggi
Guest Editors

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Keywords

cholangiocarcioma
intratumor heterogeneity
tumor microenvironment
metabolic addiction
resistance to conventional therapies
tumor–stem like cells

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Published Papers (13 papers)

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Research

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34 pages, 5879 KiB

Open AccessArticle

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

by Antonella Di Sotto, Silvia Di Giacomo, Elisabetta Rubini, Alberto Macone, Marco Gulli, Caterina Loredana Mammola, Margherita Eufemi, Romina Mancinelli and Gabriela Mazzanti

Cells 2020, 9(4), 858; https://doi.org/10.3390/cells9040858 - 2 Apr 2020

Cited by 21 | Viewed by 3632

Abstract

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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33 pages, 17453 KiB

Open AccessArticle

Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

by Ainhoa Lapitz, Ander Arbelaiz, Colm J. O’Rourke, Jose L. Lavin, Adelaida La Casta, Cesar Ibarra, Juan P. Jimeno, Alvaro Santos-Laso, Laura Izquierdo-Sanchez, Marcin Krawczyk, Maria J. Perugorria, Raul Jimenez-Aguero, Alberto Sanchez-Campos, Ioana Riaño, Esperanza Gónzalez, Frank Lammert, Marco Marzioni, Rocio I.R. Macias, Jose J. G. Marin, Tom H. Karlsen, Luis Bujanda, Juan M. Falcón-Pérez, Jesper B. Andersen, Ana M. Aransay, Pedro M. Rodrigues and Jesus M. Banales Show full author list Hide full author list

Cells 2020, 9(3), 721; https://doi.org/10.3390/cells9030721 - 14 Mar 2020

Cited by 63 | Viewed by 6615

Abstract

: Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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Review

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16 pages, 1712 KiB

Open AccessReview

A New Option for the Treatment of Intrahepatic Cholangiocarcinoma: Percutaneous Hepatic Perfusion with CHEMOSAT Delivery System

by Pier Francesco Ferrucci, Emilia Cocorocchio, Guido Bonomo, Gianluca Maria Varano, Paolo Della Vigna and Franco Orsi

Cells 2021, 10(1), 70; https://doi.org/10.3390/cells10010070 - 5 Jan 2021

Cited by 10 | Viewed by 3951

Abstract

Liver metastases are a major management problem; since they occur in tumors of different origin, they are often multiple, difficult to visualize and can lie dormant for many years. Patients with liver metastases usually die of their disease, mostly due to liver failure, since systemic treatments are unable to eradicate micro-metastasis, and interventional loco-regional procedures cannot treat all existing ones. Cholangiocarcinoma (CCA) is the second most common primary liver tumor, showing a poor overall prognosis. When resection is not possible, treatment options include tumor-focused or local ablative therapy, organ-focused or regional therapy and systemic therapy. We reviewed available loco-regional therapeutic options, with particular focus on the CHEMOSAT^® Melphalan/Hepatic Delivery System (CS-HDS), which is uniquely positioned to perform a percutaneous hepatic perfusion (PHP), in order to treat the entire liver as a standalone or as complementary therapy. This system isolates the liver circulation, delivers a high concentration of chemotherapy (melphalan), filters most chemotherapy out of the blood and is a repeatable procedure. Most CS-HDS benefits are demonstrated in liver-predominant diseases, like liver metastasis from uveal melanoma (UM), hepatocarcinoma (HCC) and CCA. More than 650 procedures have been performed in Europe to date, mostly to treat liver metastases from UM. In CCA, experience is still limited, but retrospective analyses have been reported, while phase II and III studies are closed, waiting for results or ongoing. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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18 pages, 1765 KiB

Open AccessFeature PaperReview

Necroptosis in Cholangiocarcinoma

by Samantha Sarcognato, Iris E. M. de Jong, Luca Fabris, Massimiliano Cadamuro and Maria Guido

Cells 2020, 9(4), 982; https://doi.org/10.3390/cells9040982 - 15 Apr 2020

Cited by 15 | Viewed by 5202

Abstract

Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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11 pages, 640 KiB

Open AccessFeature PaperReview

Cholangiocarcinoma Disease Modelling Through Patients Derived Organoids

by Francesco Amato, Colin Rae, Maria Giuseppina Prete and Chiara Braconi

Cells 2020, 9(4), 832; https://doi.org/10.3390/cells9040832 - 30 Mar 2020

Cited by 14 | Viewed by 5514

Abstract

Cancer organoids are 3D phenotypic cultures that can be established from resected or biopsy tumour samples and can be grown as mini tumours in the dish. Flourishing evidence supports the feasibility of patient derived organoids (PDO) from a number of solid tumours. Evidence for cholangiocarcinoma (CCA) PDO is still sparse but growing. CCA PDO lines have been established from resected early stage disease, advanced cancers and highly chemorefractory tumours. Cancer PDO was shown to recapitulate the 3D morphology, genomic landscape and transcriptomic profile of the source counterpart. They proved to be a valued model for drug discovery and sensitivity testing, and they showed to mimic the drug response observed in vivo in the patients. However, PDO lack representation of the intratumour heterogeneity and the tumour-stroma interaction. The efficiency rate of CCA PDO within the three different subtypes, intrahepatic, perihilar and distal, is still to be explored. In this manuscript we will review evidence for CCA PDO highlighting advantages and limitations of this novel disease model. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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14 pages, 2092 KiB

Open AccessReview

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

by Kishor Pant, Estanislao Peixoto, Seth Richard and Sergio A. Gradilone

Cells 2020, 9(3), 780; https://doi.org/10.3390/cells9030780 - 23 Mar 2020

Cited by 52 | Viewed by 6068

Abstract

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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13 pages, 991 KiB

Open AccessFeature PaperReview

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

by Luca Maroni, Elisabetta Ninfole, Claudio Pinto, Antonio Benedetti and Marco Marzioni

Cells 2020, 9(3), 736; https://doi.org/10.3390/cells9030736 - 17 Mar 2020

Cited by 26 | Viewed by 5047

Abstract

The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut–liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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22 pages, 3949 KiB

Open AccessReview

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

by Sara Massironi, Lorenzo Pilla, Alessandra Elvevi, Raffaella Longarini, Roberta Elisa Rossi, Paolo Bidoli and Pietro Invernizzi

Cells 2020, 9(3), 688; https://doi.org/10.3390/cells9030688 - 11 Mar 2020

Cited by 66 | Viewed by 7499

Abstract

Cholangiocarcinoma (CCA) represents a disease entity that comprises a heterogeneous group of biliary malignant neoplasms, with variable clinical presentation and severity. It may be classified according to its anatomical location and distinguished in intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), each subtype implying distinct epidemiology, biology, prognosis, and strategy for clinical management. Its incidence has increased globally over the past few decades, and its mortality rate remains high due to both its biological aggressiveness and resistance to medical therapy. Surgery is the only potentially curative treatment and is the standard approach for resectable CCA; however, more than half of the patients have locally advanced or metastatic disease at presentation. For patients with unresectable CCA, the available systemic therapies are of limited effectiveness. However, the advances of the comprehension of the complex molecular landscape of CCA and its tumor microenvironment could provide new keys to better understand the pathogenesis, the mechanisms of resistance and ultimately to identify promising new therapeutic targets. Recently, clinical trials targeting isocitrate dehydrogenase (IDH)-1 mutations and fibroblast growth factor receptor (FGFR)-2 fusions, as well as immunotherapy showed promising results. All these new and emerging therapeutic options are herein discussed. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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29 pages, 1252 KiB

Open AccessReview

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

by Hector Perez-Montoyo

Cells 2020, 9(3), 614; https://doi.org/10.3390/cells9030614 - 4 Mar 2020

Cited by 25 | Viewed by 5689

Abstract

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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28 pages, 759 KiB

Open AccessFeature PaperReview

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

by Mirella Pastore, Giulia Lori, Alessandra Gentilini, Maria Letizia Taddei, Giovanni Di Maira, Claudia Campani, Stefania Recalcati, Pietro Invernizzi, Fabio Marra and Chiara Raggi

Cells 2020, 9(3), 596; https://doi.org/10.3390/cells9030596 - 3 Mar 2020

Cited by 17 | Viewed by 4969

Abstract

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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12 pages, 562 KiB

Open AccessFeature PaperReview

Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma

by Jose J.G. Marin, Rocio I.R. Macias, Candela Cives-Losada, Ana Peleteiro-Vigil, Elisa Herraez and Elisa Lozano

Cells 2020, 9(2), 498; https://doi.org/10.3390/cells9020498 - 21 Feb 2020

Cited by 6 | Viewed by 4200

Abstract

The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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17 pages, 568 KiB

Open AccessFeature PaperReview

Neuroendocrine Changes in Cholangiocarcinoma Growth

by Keisaku Sato, Heather Francis, Tianhao Zhou, Fanyin Meng, Lindsey Kennedy, Burcin Ekser, Leonardo Baiocchi, Paolo Onori, Romina Mancinelli, Eugenio Gaudio, Antonio Franchitto, Shannon Glaser and Gianfranco Alpini

Cells 2020, 9(2), 436; https://doi.org/10.3390/cells9020436 - 13 Feb 2020

Cited by 7 | Viewed by 3639

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA—intrahepatic, hilar (perihilar), or distal (extrahepatic)—according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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14 pages, 2395 KiB

Open AccessReview

Asbestos and Intrahepatic Cholangiocarcinoma

by Giovanni Brandi and Simona Tavolari

Cells 2020, 9(2), 421; https://doi.org/10.3390/cells9020421 - 12 Feb 2020

Cited by 20 | Viewed by 6601

Abstract

The link between asbestos exposure and the onset of thoracic malignancies is well established. However epidemiological studies have provided evidences that asbestos may be also involved in the development of gastrointestinal tumors, including intrahepatic cholangiocarcinoma (ICC). In line with this observation, asbestos fibers have been detected in the liver of patients with ICC. Although the exact mechanism still remains unknown, the presence of asbestos fibers in the liver could be explained in the light of their translocation pathway following ingestion/inhalation. In the liver, thin and long asbestos fibers could remain trapped in the smaller bile ducts, particularly in the stem cell niche of the canals of Hering, and exerting their carcinogenic effect for a long time, thus inducing hepatic stem/progenitor cells (HpSCs) malignant transformation. In this scenario, chronic liver damage induced by asbestos fibers over the years could be seen as a classic model of stem cell-derived carcinogenesis, where HpSC malignant transformation represents the first step of this process. This phenomenon could explain the recent epidemiological findings, where asbestos exposure seems mainly involved in ICC, rather than extrahepatic cholangiocarcinoma, development. Full article

(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Opportunities of Cholangiocarcinoma)

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