Materiały źródłowe

• #1 Cholangiocarcinoma: Advances in Pathogenesis, Diagnosis, and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2547491/

  Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation. CCA likely results from malignant transformation of cholangiocytes, although transformation of epithelial cells within peribiliary glands and/or biliary stem cells may also contribute to its development. There is also evidence that subsets of CCA and mixed hepatocellular carcinoma/CCA originate from hepatic stem/progenitor cells. Etiologic and experimental evidence implicates inflammation and cholestasis as key factors in the pathogenesis of CCA. They create an environment that promotes damage in DNA mismatch repair genes/proteins, proto-oncogenes, and tumor suppressor genes. Cytokines, growth factors, and bile acids, found in increased concentrations in inflammation and cholestasis, contribute to these molecular changes and augment the growth and survival of altered cells. Increased iNOS activity results in generation of nitric oxide and reactive nitrogen oxide species (RNOS) known to interact with cellular DNA and proteins. The interaction between RNOS and the cellular genome results in mutations and DNA strand breaks. A variety of oncogenic mutations have been identified in human CCA tissues. Their frequency depends on tumor stage, tumor type, anatomical location, etiology, and ethnic population. Although dysregulation of the proto-oncogene k-ras and the tumor suppressor gene p53 is commonly observed in malignancies, mutations of k-ras have only been described in 20% to 54% of intrahepatic CCA. Nuclear accumulation of p53 and up-regulation of the related protein mdm-2 and WAF-1 have been reported in 21.7% to 76% of CCAs. Other inactivated tumor suppressor genes include p16INK4a, DPC4/Smad4, and APC. Correlation between these markers and prognosis varies among studies. Interleukin-6 (IL-6) appears to be a critical signaling molecule in the pathogenesis of human cancers. IL-6 is also a key cytokine in the pathogenesis of CCA. It is a known mitogen, and its proliferative effect has been confirmed in CCA. IL-6 is produced at high levels by CCA cells, and elevated IL-6 serum concentrations have been reported in CCA patients. IL-6 secretion by CCA cells is further enhanced by other inflammatory cytokines. In addition to autocrine and paracrine IL-6 stimulation, CCA cells overexpress the IL-6 receptor subunit gp130. Uninhibited IL-6 stimulation results in up-regulation of the antiapoptotic Bcl-2 protein Mcl-1, rendering CCA resistant to cytotoxic therapies. IL-6 has also been shown to increase telomerase activity in CCA resulting in inhibition of telomere shortening and thereby evasion of cell senescence. In CCA cells, IL-6 activates p44/p42 and p38 mitogen-activated protein kinases (MAPKs), both shown to be critical for CCA cell proliferation. There is also cross-communication between IL-6 and other pathways (for example, IL-6-mediated overexpression of EGFR). Mechanisms of IL-6 signaling in human CCA are depicted in Fig. 1. Receptor tyrosine kinases, which can be targeted pharmaceutically, are overexpressed in many cancers and modulate cancer biology. For example, inhibition of EGFR signaling has been shown to significantly suppress CCA cell growth. EGFR can directly be activated by bile acids and promote CCA cell proliferation, a potential explanation for the tropism exerted by CCA for the biliary tree. EGFR activation is sustained in CCA by failure to internalize the ligandreceptor complex, a homeostatic mechanism essential for receptor inactivation. EGFR phosphorylation results in activation of the downstream kinases p42/44 MAPK and p38 MAPK, which in turn increase cyclooxygenase 2 (COX-2) expression in CCA cells. COX-2 plays an important role in CCA carcinogenesis through inhibition of apoptosis and growth stimulation. Additional induction of COX-2 is mediated by bile acids, oxysterols, and iNOS. Other COX-2-inducing molecules include the tyrosine kinase ErbB-2, which is overexpressed in CCA and involved in CCA carcinogenesis and progression. It is an EGFR homologue and is able to homodimerize or heterodimerize with other members of the EGF superfamily, resulting in activation or the Raf/MAPK-pathway. Also, hepatocyte growth factor and its receptor c-met are frequently over-expressed in CCA. Hepatocyte growth factor is mitogenic, and its increased secretion by CCA cells together with the overexpression of its receptor represents an autocrine mechanism for sustained growth stimulation by CCA. In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

• #2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3862291/

  Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic (iCCA), perihilar (pCCA), or distal CCA (dCCA). […] Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to development of CCA. […] CCA frequently arises under conditions of inflammation, which is believed to contribute to pathogenesis. A variety of cytokines, growth factors, tyrosine kinases, and bile acids can contribute to the alterations in proliferation, apoptosis, senescence, and cell cycle regulation required for cholangiocarcinogenesis. […] Inflammatory signaling pathways therefore appear to promote development of CCA by causing DNA damage and blocking the apoptosis normally induced by the DNA damage response.

• #3 Cholangiocarcinoma – Wikipedia

  https://en.wikipedia.org/wiki/Cholangiocarcinoma

  Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. […] Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell. […] Cholangiocarcinoma is thought to develop through a series of stages from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma in a process similar to that seen in the development of colon cancer. […] Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.

• #4 Cholangiocarcinoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Cholangiocarcinoma_pathophysiology

  The epithelial cell lining the bile ducts are called cholangiocytes. The malignant transformsation of cholangiocytes leads to cholangiocarcinoma. Malignant transformation of cholangiocytes into cholangiocarcinoma include hyperplasia, metaplasia and dysplasia. […] Biliary intraepithelial neoplasia is believed to be the initial lesion of cholangiocarcinoma, particularly in patients with hepatolithiasis in bile ducts. […] Progression of malignancy is believed to be due to: Inflammation, Obstruction of bile ducts, Biliary intraepithelia neoplasia.

• #5

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3862291/

  A model in which iCCAs arise from trans-differentiation and subsequent neoplastic conversion of normal hepatocytes into malignant cholangiocytes has been proposed. […] A few studies have assessed the roles of genetic factors, such as chromosome aberrations or genetic and epigenetic alterations in tumor suppressor genes and oncogenes, in pathogenesis of human CCA. […] There has been growing interest in the effects of somatic mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2. […] A number of epigenetic alterations, such as promoter hypermethylation and microRNA dysregulation, have been associated with development of CCA. […] The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree. […] Another evolutionary conserved, developmental pathway is the Hedgehog signaling pathway.

• #6 Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

  https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W2028700227

  Cholangiocarcinomas (CCAs) are hepatobiliary cancers with features of cholangiocyte differentiation; they can be classified anatomically as intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA. […] Changes in oncogene and inflammatory signaling pathways, as well as genetic and epigenetic alterations and chromosome aberrations, have been shown to contribute to the development of CCA. […] Furthermore, CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts, which promotes their progression. […] We review recent developments in our understanding of the epidemiology and pathogenesis of CCA, along with advances in classification, diagnosis, and treatment. […] A model in which iCCAs arise from transdifferentiation and subsequent neoplastic conversion of normal hepatocytes into malignant cholangiocytes has been proposed.

• #7 Molecular Pathogenesis of Cholangiocarcinoma | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5391-0

  Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. […] This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. […] Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. […] Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-B pathways that encourage cell proliferation, migration and survival.

• #8 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?pn=search&uid=1029&vmd=Full

  Cholangiocarcinoma (CCA) is an epithelial malignancy originating from transformed cholangiocytes, with preclinical studies suggesting hepatic progenitor cells as cells of origin. Inflammation and cholestasis are key factors in cholangiocarcinogenesis. Proinflammatory cytokines (i.e., interleukin-6 [IL-6]) activate inducible nitric oxide synthase resulting in excess nitric oxide that mediates oxidative DNA-damage, inhibition of DNA repair enzymes and expression of cyclooxygenase 2 (COX-2). Proinflammatory pathways downregulate hepatobiliary transporters, thereby, contributing to cholestasis. Bile acids and oxysterols activate epidermal growth factor receptor (EGFR) and enhance COX-2 expression. COX-2 dysregulates CCA growth and apoptosis-resistance, and positively regulates pro-oncogenic signaling pathways such as hepatocyte growth factor (HGF), IL-6, and EGFR.

• #9 Molecular Pathogenesis of Cholangiocarcinoma: Implications for Disease Classification and Therapy

  https://www.cancernetwork.com/view/journal-molecular-pathogenesis-of-cholangiocarcinoma-implications-for-disease-classification-and-therapy

  The MAPK pathway includes several intermediaries that play a central role in carcinogenesis, and mutated forms are common drivers of CCA. These protein kinases, which include Ras, Raf, MEK, and ERK, are involved in signal transduction pathways that modulate a variety of processes that impact cellular pathophysiology. Mutations of KRAS and BRAF that result in constitutive activation of the protein kinase are particularly common. […] BRAF mutations occur in approximately 5% of CCA and are mutually exclusive from KRAS. They have been more commonly described in ICCAs. BRAF is downstream of KRAS, with the most common mutation at V600E, resulting in strong activation of RAF kinase and RAS-independent signaling. […] TP53 is a tumor suppressor gene that is also present in different types of CCA. Lowery et al observed TP53 mutations, common in multiple biliary tract malignancies and pancreatic cancer, in 49% of ECCAs and less than 20% of ICCAs. TP53 mutations are seen at a higher prevalence in fluke-related CCA and hepatitis B antigen seropositive patients.

• #10 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?pn=search&uid=1029&vmd=Full

  Next generation sequencing identified somatic mutations in oncogenes (i.e., KRAS), tumor suppressor (i.e., TP53 and SMAD4) and chromatin modifying genes (i.e., ARID1A, BAP1, and PBMR1) in CCA. These studies have also shown the distinct mutational landscape of different etiologies and anatomic locations. KRAS mutations are more common in pCCA (22% to 53%) than iCCA (9% to 17%), while IDH1/2 mutations are more characteristic of iCCA. Mutant IDH1/2 (isocitrate dehydrogenase) inhibits hepatocyte but not biliary differentiation and causes expansion of hepatic progenitor cells, resulting in iCCA-formation in genetic mouse models. Liver fluke-associated CCA is more commonly associated with mutations of TP53 and SMAD4, while BAP1 and IDH1/2 mutations are more frequent in non-liver fluke associated CCA. Mutations of genes coding for components of oncogenic pathways such as PI3KCA and MET have been described in iCCA and pCCA. Recently, gene rearrangements resulting in oncogenic fibroblast growth factor 2 (FGFR2) fusion proteins were identified in up to 45% of iCCA patients. Also nongenomic upregulation of EGFR, human epidermal growth factor receptor 2 (HER2) and MET was found, especially in patients with poor outcomes. Whole-genome expression profiling confirmed activation of pathways driving proliferation (i.e., EGF, RAS, AKT, and MET), angiogenesis (i.e., vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor) and inflammation (i.e., IL-6).

• #11 Molecular Pathogenesis of Cholangiocarcinoma: Implications for Disease Classification and Therapy

  https://www.cancernetwork.com/view/journal-molecular-pathogenesis-of-cholangiocarcinoma-implications-for-disease-classification-and-therapy

  FGFR mutations, amplification, and gene rearrangements including translocations and intragenic deletions have been described in a wide variety of human malignancies. Clonal FGFR2 gene fusions in CCA lead to ligand-independent activation of multiple signaling networks including the MAPK, PI3K-AKT, JAK-STAT, and protein kinase C pathways that in turn promote tumor progression through enhanced malignant cell proliferation, migration, and survival, as well as angiogenesis. […] IDH1 and IDH2 are metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to -ketoglutarate and are mutated in a variety of human malignancies. Missense mutations in the R132 codon of IDH1 are present in 13% to 20% of intrahepatic CCAs (ICCAs) and rarely in extrahepatic CCAs (ECCAs) and perihilar CCAs, resulting in excess production of the oncometabolite R-2-hydroxyglutarate (R-2HG). R-2HG accumulation modifies the epigenetic state of tumor progenitor cells by altering DNA and histone methylation patterns, thereby inhibiting cellular differentiation and promoting oncogenesis.

• #12 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?pn=search&uid=1029&vmd=Full

  Receptor tyrosine kinases such as IL-6 receptor, c-MET and the EGFR family members ERBB2 and ERBB1 are key signaling pathways in cholangiocarcinogenesis. CCA cells and cancer-associated fibroblasts express and secrete cytokines and other mitogenic growth factors (i.e., IL-6 and HGF) with subsequent auto- and paracrine stimulation of their cognate receptors. Receptor-overexpression (i.e., IL-6R, c-MET, and EGFR), inactivation of negative feedback mechanisms, and transactivation between receptors (i.e., c-MET/EGFR and COX-2/IL-6) further contribute to constitutive pathway activation. Aberrant activation of these receptor tyrosine kinases causes constitutive activation of downstream signaling cascades (i.e., Janus kinase [JAK]/signal transducer and activator of transcription 3 [STAT3], PI3K/Akt, ERK1/2, and p38MAPK) resulting in dysregulation of cell senescence, cell cycle regulation and proliferation, and apoptosis.

• #13 Pathology and molecular pathology of cholangiocarcinoma

  https://www.oaepublish.com/articles/2394-5079.2021.89

  Biliary tract cancers are a wide group of heterogeneous neoplasms of the biliary tree, composed of intrahepatic cholangiocarcinoma perihilar bile duct cancer and distal bile duct cancer, according to location. The variability in location reflects the different morphologies and molecular alterations. […] Recently, molecular targetable alterations, mainly FGFR2 fusions and IDH1 mutations, have been described, mostly in the intrahepatic small duct type subgroup and have opened the way, together with rarer targetable alterations, for personalisation of therapy also in these aggressive neoplasms. […] Important targetable molecular alterations have recently been described, regarding around 15%-20% of the intrahepatic cholangiocarcinoma, whilst the extrahepatic bile duct cancer is rarely a suitable subject for targeted therapy. These aberrations are FGFR2 fusions, IDH1/2 mutations, more rarely BRAF V600E and BRCA1/2 alterations, neurotrophic receptor tyrosine kinase (NTRK) fusions and microsatellite instability (MSI).

• #14 Pathology and molecular pathology of cholangiocarcinoma

  https://www.oaepublish.com/articles/2394-5079.2021.89

  Since 2014, the biliary tract cancers have been discovered to be targetable because of distinctive molecular alterations that can be found in around 50% of cases in large series, allowing patients to have more chances to be treated also when relapsing and opening the way to personalisation of therapies. […] The targetable alterations mainly regard FGFR2 and IDH1, representing around 20% and 15% of cases, respectively. […] FGFR2 rearrangements seems to occur mainly in young adults and possibly confer a better prognosis. […] IDH1 alterations are missense mutations that generally involve a single residue in the active site of the enzyme. […] Fusion events can involve the NTRK kinase (NTRK 1-3 genes) with different upstream partners, leading to the overexpression of chimeric protein and constitutively active, ligand-independent downstream signalling.

• #15 Pathology and molecular pathology of cholangiocarcinoma

  https://www.oaepublish.com/articles/2394-5079.2021.89

  MSI is found in around 5% of iCCAs, sometimes occurring in Lynch syndrome. […] BRCA mutations are found in around 3.6% of iCCAs without differences in terms of site, providing rationale for targeted therapies. […] Another rare mutation (1%) regards BRAFV600E, which can be detectable with immunohistochemistry and/or directly investigated with DNA-based methods. […] Rarely, HER2 can be found overexpressed by immunohistochemistry in biliary tract cancer (around 1.4% in a large study), more commonly in distal bile duct cancer, and its detection requires screening with immunohistochemistry and confirmation with FISH. […] Concerning eCCAs, as mentioned above, they rarely show targetable alterations tending to be similar to pancreatic adenocarcinoma, with mutations regarding TP53, KRAS and SMAD4.

• #16 Molecular Pathogenesis of Cholangiocarcinoma: Implications for Disease Classification and Therapy

  https://www.cancernetwork.com/view/journal-molecular-pathogenesis-of-cholangiocarcinoma-implications-for-disease-classification-and-therapy

  The TME consists of heterogeneous cell types including tumor-infiltrating lymphocytes (TILs) and natural killer cells; cancer-associated fibroblasts (CAFs); tumor-associated macrophages (TAMs) and myeloid cells; endothelial cells and pericytes; and a desmoplastic extracellular matrix (ECM) consisting of proteoglycans and soluble factors. A variety of treatment strategies directed against various constituents of the TME are being explored.

• #17

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3862291/

  Carcinogenesis in CCA includes alterations in the stroma, recruitment of fibroblasts, remodeling of the extracellular matrix(ECM), changing patterns of immune cell migration, and promotion of angiogenesis. […] The tumor stroma surrounds the malignant ducts and glands and comprises most of the tumor mass. […] The precise origin of CAFs is unclear, although several cell types, including hepatic stellate cells, portal fibroblasts, and bone-marrow derived precursor cells, have been proposed as candidates. […] The exact mechanisms by which tumor and stroma communicate are not clear. However, the importance of the desmoplastic stroma in CCA progression indicates that it could be a new therapeutic target, perhaps via selective targeting of CAFs.

• #18 Cholangiocarcinoma: Advances in Pathogenesis, Diagnosis, and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2547491/

  The growing understanding of the molecular pathogenesis of CCA opens new therapeutic options for molecular targeting. The majority of these strategies target antiapoptotic and growth-stimulating pathways. The use of methylation inhibitors is able to restore SOCS-3 expression, thereby reducing protein expression of the prosurvival bcl-2 family protein Mcl-1 and sensitizing CCA cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Other strategies for inhibiting Mcl-1 expression include the use of the multikinase inhibitor sorafenib and overexpression of mir-29 microRNA. Small molecules such as obatoclax are also in development to inhibit Mcl-1. Sensitization of CCA cells to TRAIL was also achieved through the use of a -secretase inhibitor to inhibit Notch signaling. Tyrosine kinase inhibitors have been used to target EGFR signaling and reduce tumor cell growth. Inhibition of IL-6 pathways by anti-IL-6 neutralizing antibodies or MAPK inhibitors results in growth inhibition of human CCA cell lines. Other strategies including COX-2 inhibitors, hepatocyte growth factor antagonists, ErbB-1/2 inhibition, and telomerase inhibition achieved growth inhibition and/or induction or sensitization to apoptosis in vitro. These examples show the promising potential of these new therapeutic approaches. However, the vast majority of these studies were conducted in vitro. Though the preliminary in vivo results are promising, the majority of in vivo studies have focused on tumor inhibition rather than on treatment of established tumors. Better in vivo models of CCA will be necessary to study targeted therapies.

• #19 What new research is being done in bile duct cancer treatment? | MD Anderson Cancer Center

  https://www.mdanderson.org/cancerwise/a-next-generation-treatment-for-bile-duct-cancer.h00-159622590.html

  FGFR inhibitors often stop working after a few months because the cancer acquires new genetic mutations it essentially evolves to become resistant to the medication. […] Tinengotinib, on the other hand, has a unique binding mechanism away from the ATP binding pocket that enables it to target even newly resistant cancer cells. It overcomes acquired resistance by targeting FGFR2 kinase domain mutations. Essentially, by inhibiting a number of different kinases (a particular type of enzyme important for cell growth), the drug targets the spread of the cancer cells with their acquired resistant mutations. […] These new treatments highlight the need to better understand each patients cancer genetics at different points in time.

• #20 Study uncovers mechanism behind effectiveness of three-drug combination in patients with a rare bile duct cancer | Center for Cancer Research

  https://ccr.cancer.gov/news/article/study-uncovers-mechanism-behind-effectiveness-of-three-drug-combination-in-patients-with-a-rare-bile-duct-cancer

  Adding a vascular endothelial growth factor (VEGF) inhibitor to a treatment regimen of two therapies known as immune checkpoint inhibitors stimulated the immune system more effectively and led to better tumor control than the two treatments alone, according to new research published in Immunity on April 8, 2025. This seemed to be due to increased activation of immune system B cells as well as several other types of immune cells in cholangiocarcinoma, a rare type of bile duct cancer, the study found. […] What the researchers ultimately determined was that the treatment created a chain of events: the drugs sparked different modes of activity which were dependent on a protein called BAFF, or B-cell activating factor. These activities led to an inflammatory response by an increased number of B cells that also caused production of interleukin-12 (IL-12) proteins. BAFF and IL-12 then helped rewire a type of suppressive immune cell, regulatory T cells, to become active immune cells. […] Overall, the studies showed that treatment with the triple therapy regimen resulted in delayed tumor growth and prolonged survival compared to other treatments, including anti-CTLA4 and anti-PD-L1 alone in mice and people with cholangiocarcinoma, due to this cascade of immune system effects.

• #21 Cholangiocarcinoma: Epidemiology, Pathogenesis, and Prognosis | SpringerLink

  https://link.springer.com/10.1007/978-3-030-41683-6_13

  Cholangiocarcinogenesis is driven by a complex multistep process beginning with chronic biliary tract inflammation followed by exposure to carcinogenic molecules and overexpression of proliferative growth factors. […] This results in stepwise accumulation of genetic mutations, ultimately leading to uncontrolled cell growth and metastasis.

• #22 Cholangiocarcinoma 2020: the next horizon in mechanisms and management | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/s41575-020-0310-z

  Growing evidence demonstrates that distinct cells of origin within an organ can give rise to different subtypes of cancer, typically tissue-specific stem and progenitor cells. Evidence regarding the cells of origin of CCA in humans was obtained by phenotyping the candidate tissues and/or cells of origin with respect to CCA subtypes through histological and gene expression analysis, whereas indirect evidence might be derived from risk factors. […] Cholangiocarcinogenesis is orchestrated by a complex interplay of extracellular ligands (such as pro-inflammatory cytokines, growth factors and bile acids, among others), which are present in the tumour microenvironment (TME), and increased expression and/or aberrant activation of cell surface receptors and the deregulation of intracellular signalling pathways, finally leading to cell proliferation, survival and genetic and/or epigenetic alterations. Chronic inflammation and fibrosis facilitate cholangiocyte transformation in a multistep manner, providing extracellular ligands that modulate several signalling pathways.

• #23 Cholangiocarcinoma 2020: the next horizon in mechanisms and management | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/s41575-020-0310-z

  CCA often arises in the setting of prolonged biliary inflammation and/or cholestasis, which contribute to carcinogenesis. According to transcriptomic profiles, the inflammation and proliferation subtypes of iCCA were previously identified and reported to be differentially enriched with activation of the pro-inflammatory and oncogenic pathways, respectively. The inflammation subclass of tumours was characterized by induction of immune-related signalling pathways. By contrast, the proliferation subclass was enriched in classic oncogenic pathways, including deregulated receptor tyrosine kinase (RTK) signalling, RAS-RAF-ERK, PI3K-AKT-mTOR, insulin growth factor receptor 1, MET, polo-like kinase 1, aurora kinase A, KRAS mutations and stem-like genomic traits as well as a focal deletion in the Hippo pathway (SAV1).

• #24 Molecular Pathogenesis of Cholangiocarcinoma | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5391-0

  Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. […] Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. […] An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.

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