Materiały źródłowe

• #1

  https://link.springer.com/article/10.1007/s11684-010-0130-6

  Hilar cholangiocarcinoma, first described by Klatskin in 1965, is a relatively rare tumor arising from the bile ducts. […] The development of cholangiocarcinoma is a multistep process associated with several mutations in oncogenes and tumor-suppressor genes. […] Hilar cholangiocarcinoma is a slowly growing tumor and tends to spread longitudinally along the bile ducts with neural, perineural, and subepithelial extension. […] Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. […] Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. […] Mechanisms of biliary carcinogenesis and growth. […] Inflammatory cytokines suppress NAD(P)H:quinone oxidoreductase-1 and induce oxidative stress in cholangiocarcinoma cells.

• #2 Surgical management of hilar cholangiocarcinoma: Controversies and recommendations

  https://www.ahbps.org/journal/view.html?doi=10.14701/ahbps.23-028

  Cholangiocarcinoma is a rare tumor of the bile duct epithelium that accounts for only 3% of gastrointestinal malignancies. It has been divided into intrahepatic, hilar, and extrahepatic lesions, of which the hilar variety is the most common variant. Hilar cholangiocarcinoma (HC) was initially described by Altemeier et al. in 1957, but was popularized by Klatskin in 1965. He described a peri-operative mortality of 92%, which has now been reduced to 8% by the advent of more sophisticated imaging procedures, an improvement of surgical techniques, and by preoperative interventions like biliary drainage to reduce the levels of jaundice and portal vein embolization (PVE) to cause hypertrophy of the remnant liver, if it is judged to be inadequate after a major resection is performed. However, even after 50 years operations for the tumor, its management remains a challenge for the surgeon.

• #3 Cholangiocarcinoma – Wikipedia

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

  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. […] Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell.

• #4 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. […] Molecular pathogenesis of cholangiocarcinoma. […] Molecular mechanisms of cholangiocarcinoma. […] Hilar cholangiocarcinoma: diagnosis, treatment options, and management. […] Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. […] Predictors of long term survival after hepatic resection for hilar cholangiocarcinoma: a retrospective study of 5-year survivors. […] The clinicopathological factors associated with prognosis of patients with resectable perihilar cholangiocarcinoma. […] Disease recurrence patterns after R0 resection of hilar cholangiocarcinoma. […] Predictive factors of early recurrence after R0 resection of hilar cholangiocarcinoma a single institution experience in China.

• #5 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. […] Molecular pathogenesis of cholangiocarcinoma. […] Molecular mechanisms of cholangiocarcinoma. […] Hilar cholangiocarcinoma: diagnosis, treatment options, and management. […] Hilar cholangiocarcinoma: tumor depth as a predictor of outcome. […] Predictors of long term survival after hepatic resection for hilar cholangiocarcinoma: a retrospective study of 5-year survivors. […] The clinicopathological factors associated with prognosis of patients with resectable perihilar cholangiocarcinoma. […] Disease recurrence patterns after R0 resection of hilar cholangiocarcinoma. […] Predictive factors of early recurrence after R0 resection of hilar cholangiocarcinoma a single institution experience in China.

• #6 Pathology of intrahepatic cholangiocarcinoma – Vijgen – Hepatobiliary Surgery and Nutrition

  https://hbsn.amegroups.org/article/view/12734/13979

  Intrahepatic cholangiocarcinoma (iCC) is a primary carcinoma of the liver with increasing significance and major pathogenic, clinical and therapeutic challenges. Classically, it arises from malignant transformation of cholangiocytes bordering small portal bile duct (BD) to second-order segmental large BDs. […] Several different cells of origin have also been depicted in a fraction of iCCs, amongst which malignant transformation of ductules, of hepatic stem/progenitor cells, of periductal glands or through oncogenic reprogramming of adult hepatocytes. A degree of pathological overlap with hepatocellular carcinoma (HCC) may be observed in a portion of iCC. A series of precursor lesions are today characterized and emphasize the existence of a multistep carcinogenesis process. […] Overall, these new data have brought up in proposal of new histological or molecular classifications, which could soon replace current anatomic-based classification and could have major impact on establishment of prognosis and on development of novel target treatment approaches.

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

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

  Cholangiocarcinoma (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. […] 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.

• #8 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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 Cholangiocarcinoma: Advances in Pathogenesis, Diagnosis, and Treatment

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

  Cholangiocarcinoma (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. […] 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.

• #10 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.

• #11

  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.

• #12 Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

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

  These studies indicate that multiple cell types, rather than only cholangiocytes, transform and develop into CCAs. […] Inflammatory signaling pathways therefore appear to promote the development of CCA by causing DNA damage and blocking the apoptosis normally induced by the DNA damage response. […] Additional studies are necessary to verify these potential associations.

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

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

  Cholangiocarcinoma (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. […] 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.

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

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

  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. […] 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. […] Thus, despite shared developmental ontology between the pancreatic ducts and the biliary tree, their adult cancers are different. […] Other dysregulated genes/factors involved in cell cycle regulation and found in CCA are listed in Table 2. […] 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.

• #15 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.

• #16 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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.

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

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

  iCCA can show three main patterns of growth: mass-forming, periductal-infiltrating, and intraductal-growing. […] Histologically, although the vast majority of pCCA and dCCA are conventional mucin-producing adenocarcinomas or papillary tumours, iCCA shows several histological variants. […] The activation of these signalling pathways might also occur as a result of the interaction between the tumour epithelia and the tumour reactive stroma. […] Chronic inflammation and fibrosis facilitate cholangiocyte transformation in a multistep manner, providing extracellular ligands that modulate several signalling pathways. […] The process of cholangiocarcinogenesis, and further tumour evolution and growth, involves complex and heterogeneous processes that include the interplay of extracellular ligands, which are present in the tumour microenvironment, 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.

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

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

  IL-6 secretion by CCA cells is further enhanced by other inflammatory cytokines. […] 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 summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

• #19 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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. […] 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.

• #20 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?uid=1029&vmd=Full&bodyNum=05

  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. […] 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.

• #21 Cholangiocarcinoma pathogenesis: Role of the tumor microenvironment – Leyva-Illades – Translational Gastrointestinal Cancer

  https://tgc.amegroups.com/article/view/76/68

  Cholangiocarcinoma is a tumor that originates from the neoplastic transformation of the epithelial cells of the intrahepatic or extrahepatic bile ducts. […] Its pathogenesis is poorly understood, however it is known that the tumor microenvironment is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis. […] The tumor microenvironment is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis; however, the mechanisms by which these events are regulated remain mostly unknown. […] The interaction between the cancer cells and stromal cells of the microenvironment is bi-directional and dynamic. […] The immune cells present in the tumor microenvironment, tumor-associated macrophages in particular, can confer resistance to toxic insults in addition to promoting growth.

• #22 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.

• #23 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. […] Interactions between malignant cells and TILs promote tumor progression in part through the activation of immune checkpoints including PD-1 (and its ligand PD-L1) and CTLA-4 that result in exhaustion of cytotoxic CD8+ lymphocytes and upregulation of CD4+CD25+FOXP3+ regulatory T cells. […] The combination of trastuzumab and pertuzumab resulted in a response rate of 23% in HER2-amplified or -overexpressed metastatic biliary tract cancer previously treated, which included CCA. […] Strategies targeting p53 include degradation of mutant p53, restoration of wild-type p53 through epigenetic modification and clustered regularly interspaced short palindromic repeats technology, and immunotherapy targeting cells expressing mutant TP53.

• #24 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. […] Interactions between malignant cells and TILs promote tumor progression in part through the activation of immune checkpoints including PD-1 (and its ligand PD-L1) and CTLA-4 that result in exhaustion of cytotoxic CD8+ lymphocytes and upregulation of CD4+CD25+FOXP3+ regulatory T cells. […] The combination of trastuzumab and pertuzumab resulted in a response rate of 23% in HER2-amplified or -overexpressed metastatic biliary tract cancer previously treated, which included CCA. […] Strategies targeting p53 include degradation of mutant p53, restoration of wild-type p53 through epigenetic modification and clustered regularly interspaced short palindromic repeats technology, and immunotherapy targeting cells expressing mutant TP53.

• #25 Cholangiocarcinoma pathogenesis: Role of the tumor microenvironment – Leyva-Illades – Translational Gastrointestinal Cancer

  https://tgc.amegroups.com/article/view/76/68

  Targeting the molecular signals released by these cells, in addition to strategies to suppress cholangiocarcinoma cell proliferation, could aid in cholangiocarcinoma treatment. […] Recent studies have shown that myofibroblast-derived platelet-derived growth factor protects cholangiocarcinoma cells from TRAIL-induced cell death via a hedgehog dependent mechanism in vitro and in vivo. […] Cholangiocarcinoma cells are known to overproduce many inflammatory cytokines, however, IL-6 is the most studied to date. […] Collectively, these data support the hypothesis that TAMs may play a role in cholangiocarcinoma progression. […] In summary, the research discussed in the present review highlights the role that the tumor microenvironment plays in the growth, progression, and metastatic invasion of cholangiocarcinoma.

• #26 Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma

  https://www.oaepublish.com/articles/2394-5079.2023.53

  The iCCA is characterized by a dense desmoplastic stroma, the main cellular component of which is CAF expressing a-smooth muscle actin (a-SMA). […] CAFs promote not only tumor growth and invasion but also angiogenesis through the release of several molecules, such as VEGF, fibroblast growth factor (FGF), and interleukin-6 (IL-6). […] The iCCA was previously considered a hypovascular tumor in contrast to hepatocellular carcinoma (HCC). […] It is clear that tumor angiogenesis is marked in iCCA and is a feature enhancing biological aggressiveness and metastatic capacity. […] Further knowledge of angiogenic factors and their role in iCCA is needed to better understand how they may influence the progression and, eventually treatment of this tumor. […] The role of angiogenic factors and their complex interactions in iCCA progression are discussed in the following paragraphs.

• #27 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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. […] 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).

• #28 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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. […] 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).

• #29 Cholangiocarcinoma: Current Knowledge and New Developments

  https://www.gutnliver.org/journal/view.html?doi=10.5009/gnl15568

  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. […] 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).

• #30 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.

• #31 Multi-Disciplinary Care of Hilar Cholangiocarcinoma: Review of Guidelines and Recent Advancements

  https://www.mdpi.com/2072-6694/16/1/30

  While most sequencing studies group HC and distal CCA together for analysis, one study suggested that HC has a distinct molecular subtype. High-frequency HC subtype-specific mutations include TP53, KRAS, mTOR, ABL1, NOTCH1, PBRM1, PIK3CA, ARID1A, NF1, and EGFR. The prevalence of EGFR mutations supports future investigation of tyrosine kinase inhibitors as a potential therapeutic option. Other genes with a lower prevalence of mutations included ATM, CHEK1, BRCA1, and BRCA2. Targetable mutations in HC were recently identified in MAP3K9, similar to lung cancer. Mutations in mTOR and ABL1 may contribute to oncogenesis in HC.

• #32

  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. […] The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree. […] Notch dysregulation has also been implicated in cholangiocarcinogenesis. […] Another evolutionary conserved, developmental pathway is the Hedgehog signaling pathway. […] Wnt signaling is also required for intrahepatic bile duct development and proliferation. […] The tumor stroma promotes tumor progression, via reciprocal communication between the stromal cells and cancer cells. […] 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 combination of DNA damage, evasion of apoptosis, and cell proliferation are all components of cell transformation. […] Further studies are necessary to elucidate the role of genetic aberrations, particularly in regions encoding key components of signaling pathways.

• #33 Intrahepatic and Hilar Cholangiocarcinomas: Epidemiology, Basic Principles of Treatment, and Clinical Data | Oncohema Key

  https://oncohemakey.com/intrahepatic-and-hilar-cholangiocarcinomas-epidemiology-basic-principles-of-treatment-and-clinical-data/

  Interestingly, it has recently been determined that in the setting of intrahepatic disease, these processes of cholangiocarcinoma development may affect not only cholangiocytes as precursor cells, but also mature hepatocytes. […] This concept is supported by the malignant transformation of mature hepatocytes into intrahepatic cholangiocarcinoma cells in the setting of overexpression of activated Notch1 and AKT in preclinical models. […] Similar studies have confirmed biliary epithelial cells as a progenitor of intrahepatic cholangiocarcinoma as well, indicating this subset of cholangiocarcinoma may originate from various cell types, and that Notch pathway activation plays an important role in cholangiocarcinoma pathogenesis. […] Somatic mutations associated with aberrant cell signaling have also been associated with cholangiocarcinoma pathogenesis.

• #34

  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. […] The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree. […] Notch dysregulation has also been implicated in cholangiocarcinogenesis. […] Another evolutionary conserved, developmental pathway is the Hedgehog signaling pathway. […] Wnt signaling is also required for intrahepatic bile duct development and proliferation. […] The tumor stroma promotes tumor progression, via reciprocal communication between the stromal cells and cancer cells. […] 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 combination of DNA damage, evasion of apoptosis, and cell proliferation are all components of cell transformation. […] Further studies are necessary to elucidate the role of genetic aberrations, particularly in regions encoding key components of signaling pathways.

• #35

  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. […] The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree. […] Notch dysregulation has also been implicated in cholangiocarcinogenesis. […] Another evolutionary conserved, developmental pathway is the Hedgehog signaling pathway. […] Wnt signaling is also required for intrahepatic bile duct development and proliferation. […] The tumor stroma promotes tumor progression, via reciprocal communication between the stromal cells and cancer cells. […] 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 combination of DNA damage, evasion of apoptosis, and cell proliferation are all components of cell transformation. […] Further studies are necessary to elucidate the role of genetic aberrations, particularly in regions encoding key components of signaling pathways.

• #36 Fas counterattack in cholangiocarcinoma: A mechanism for immune evasion in human hilar cholangiocarcinomas

  https://www.wjgnet.com/1007-9327/full/v7/i6/860.htm

  AIM: To investigate FasL expression in hilar cholangiocarcinoma tissues and cultured cholangiocarcinoma cells, and to assess its ability to induce apoptosis. […] Hilar cholangiocarcinomas may elude immunological surveillance by inducing, via Fas/FasL system, the apoptosis of activated lymphocytes. […] The expression of FasL potentially enables hilar cholangiocarcinomas to counterattack and kill antitumor immune effector cells that seem Fas sensitive. […] Functional FasL expressed in hilar cholangiocarcinomas was recognized as a contributor to the immune evasion of hilar cholangiocarcinoma. […] The fact that extensive expression (≥ 70% of the tumor area) occurred in all tumors irrespective of tumor stage or degree of differentiation suggests that FasL may be expressed throughout hilar cholangiocarcinoma progression.

• #37 Fas counterattack in cholangiocarcinoma: A mechanism for immune evasion in human hilar cholangiocarcinomas

  https://www.wjgnet.com/1007-9327/full/v7/i6/860.htm

  Our findings have conclusively show that human hilar cholangiocarcinomas express functional FasL. […] The high prevalence of FasL expression in the tumors suggests that this molecule may be critical to tumor immune privilege. […] In conclusion, the Fas counterattack appears to prevail as a potentially critical mechanism of immune privilege in human hilar cholangiocarcinoma.

• #38 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. […] The role of Immunotherapy is emerging and offers improved survival for irresectable hilar cholangiocarcinoma. […] The causes of hCCA remain obscure in many patients. […] The estimated lifetime incidence of CCA with primary sclerosing cholangitis (PSC) ranges up to 20%. […] While PSC is a known risk factor for CCA, it is attributed to no more than 10% of CCA cases. […] Hepatobiliary flukes, specifically Opisthorchis viverrini and Clonorchis sinensis have been linked to the development of CCA in Southeast Asia, regardless of site. […] The presence of hepatitis B virus (commonly known as HBV) and hepatitis C virus (commonly known as HCV) has been linked to an increased risk of developing iCC. […] Studies do not confirm the association of HBV or HCV with hCCA.

• #39 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. […] The role of Immunotherapy is emerging and offers improved survival for irresectable hilar cholangiocarcinoma. […] The causes of hCCA remain obscure in many patients. […] The estimated lifetime incidence of CCA with primary sclerosing cholangitis (PSC) ranges up to 20%. […] While PSC is a known risk factor for CCA, it is attributed to no more than 10% of CCA cases. […] Hepatobiliary flukes, specifically Opisthorchis viverrini and Clonorchis sinensis have been linked to the development of CCA in Southeast Asia, regardless of site. […] The presence of hepatitis B virus (commonly known as HBV) and hepatitis C virus (commonly known as HCV) has been linked to an increased risk of developing iCC. […] Studies do not confirm the association of HBV or HCV with hCCA.

• #40 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. […] The role of Immunotherapy is emerging and offers improved survival for irresectable hilar cholangiocarcinoma. […] The causes of hCCA remain obscure in many patients. […] The estimated lifetime incidence of CCA with primary sclerosing cholangitis (PSC) ranges up to 20%. […] While PSC is a known risk factor for CCA, it is attributed to no more than 10% of CCA cases. […] Hepatobiliary flukes, specifically Opisthorchis viverrini and Clonorchis sinensis have been linked to the development of CCA in Southeast Asia, regardless of site. […] The presence of hepatitis B virus (commonly known as HBV) and hepatitis C virus (commonly known as HCV) has been linked to an increased risk of developing iCC. […] Studies do not confirm the association of HBV or HCV with hCCA.

• #41 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Cirrhosis is consistently identified as a risk factor for iCC but not for hCCA. […] In a meta-analysis by Clements et al, choledocholithiasis showed a stronger association with eCCA than iCCA. […] Available cohort and case-control studies indicate that high levels of alcohol consumption and tobacco smoking can also increase the likelihood of developing CCA, including hCCA. […] Conditions such as diabetes, obesity, non-alcoholic fatty liver disease and metabolic syndrome are believed to contribute to the increasing incidence of CCA. […] The role of genetic factors needs to be better defined. […] The presence of choledochal cysts conferred the most significant risk of both iCCA and eCCA.

• #42 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Cirrhosis is consistently identified as a risk factor for iCC but not for hCCA. […] In a meta-analysis by Clements et al, choledocholithiasis showed a stronger association with eCCA than iCCA. […] Available cohort and case-control studies indicate that high levels of alcohol consumption and tobacco smoking can also increase the likelihood of developing CCA, including hCCA. […] Conditions such as diabetes, obesity, non-alcoholic fatty liver disease and metabolic syndrome are believed to contribute to the increasing incidence of CCA. […] The role of genetic factors needs to be better defined. […] The presence of choledochal cysts conferred the most significant risk of both iCCA and eCCA.

• #43 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Cirrhosis is consistently identified as a risk factor for iCC but not for hCCA. […] In a meta-analysis by Clements et al, choledocholithiasis showed a stronger association with eCCA than iCCA. […] Available cohort and case-control studies indicate that high levels of alcohol consumption and tobacco smoking can also increase the likelihood of developing CCA, including hCCA. […] Conditions such as diabetes, obesity, non-alcoholic fatty liver disease and metabolic syndrome are believed to contribute to the increasing incidence of CCA. […] The role of genetic factors needs to be better defined. […] The presence of choledochal cysts conferred the most significant risk of both iCCA and eCCA.

• #44 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Cirrhosis is consistently identified as a risk factor for iCC but not for hCCA. […] In a meta-analysis by Clements et al, choledocholithiasis showed a stronger association with eCCA than iCCA. […] Available cohort and case-control studies indicate that high levels of alcohol consumption and tobacco smoking can also increase the likelihood of developing CCA, including hCCA. […] Conditions such as diabetes, obesity, non-alcoholic fatty liver disease and metabolic syndrome are believed to contribute to the increasing incidence of CCA. […] The role of genetic factors needs to be better defined. […] The presence of choledochal cysts conferred the most significant risk of both iCCA and eCCA.

• #45 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Cirrhosis is consistently identified as a risk factor for iCC but not for hCCA. […] In a meta-analysis by Clements et al, choledocholithiasis showed a stronger association with eCCA than iCCA. […] Available cohort and case-control studies indicate that high levels of alcohol consumption and tobacco smoking can also increase the likelihood of developing CCA, including hCCA. […] Conditions such as diabetes, obesity, non-alcoholic fatty liver disease and metabolic syndrome are believed to contribute to the increasing incidence of CCA. […] The role of genetic factors needs to be better defined. […] The presence of choledochal cysts conferred the most significant risk of both iCCA and eCCA.

• #46 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.

• #47 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

  Cholangiocarcinomas are an aggressive group of heterogeneous malignancies that affect over 210,000 individuals globally each year. Their incidence is rising, particularly in Western countries. Traditionally, cholangiocarcinomas are classified based on anatomic location of the tumor and are treated with similar cytotoxic chemotherapy despite significant molecular and genomic differences. With the rise of genetic and molecular sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches. The most common genomic alterations include changes in FGFR2, IDH1, KRAS, BRAF, HER2, and the tumor suppressor p53. […] The identification of mutations in oncogenes functionally relevant to the initiation and progression of CCA has led to the development of targeted therapies that are now approved for routine clinical use.

• #48 Multi-Disciplinary Care of Hilar Cholangiocarcinoma: Review of Guidelines and Recent Advancements

  https://www.mdpi.com/2072-6694/16/1/30

  Cholangiocarcinoma (CCA) is a rare malignancy of the intrahepatic and extrahepatic biliary ducts. CCA is primarily defined by its anatomic location: intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma. Hilar cholangiocarcinoma (HC) is a subtype of extrahepatic cholangiocarcinoma that arises from the common hepatic bile duct and can extend to the right and/or left hepatic bile ducts. […] Given the tumor heterogeneity associated with CCA, research has focused on developing effective targeted therapies. Targeted therapy carries a better side effect profile than cytotoxic chemotherapy and can be personalized based on the tumor’s genomic landscape. As such, molecular profiling should be performed in patients with advanced HC and patients should be referred to clinical trials as appropriate.

• #49 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. […] 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.

• #50 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. […] Interactions between malignant cells and TILs promote tumor progression in part through the activation of immune checkpoints including PD-1 (and its ligand PD-L1) and CTLA-4 that result in exhaustion of cytotoxic CD8+ lymphocytes and upregulation of CD4+CD25+FOXP3+ regulatory T cells. […] The combination of trastuzumab and pertuzumab resulted in a response rate of 23% in HER2-amplified or -overexpressed metastatic biliary tract cancer previously treated, which included CCA. […] Strategies targeting p53 include degradation of mutant p53, restoration of wild-type p53 through epigenetic modification and clustered regularly interspaced short palindromic repeats technology, and immunotherapy targeting cells expressing mutant TP53.

• #51 A long-term survivor of hilar cholangiocarcinoma with resection of recurrent peritoneal dissemination after R0 surgery: a case report | Surgical Case Reports | Full Text

  https://surgicalcasereports.springeropen.com/articles/10.1186/s40792-017-0386-z

  Adjuvant chemotherapy has not been standardized for cholangiocarcinoma, although GEM plus cisplatin is effective for advanced cholangiocarcinoma. […] The recurrent tumor in our patient was also well-differentiated. Tumor microenvironment also affects susceptibility to anticancer drugs. […] Several reports showed that tumor-infiltrating T cell including CD8+ T cell after chemotherapy was a predictor of good response to chemotherapy. […] Therefore, CD8+ T cell accumulation in cancers can lead to better clinical outcome. […] We also found that a risk-signature including CD8+ T cell status predict prognosis and sensitivity to chemotherapy after curative resection in extrahepatic cholangiocarcinoma. […] Persistent chemotherapy seemed effective for a long period in this case, and we need to explore predictive factors for such successful chemotherapy based on the pharmaceutical mechanism of each chemotherapeutic agent.

• #52 National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

  https://www.wjgnet.com/1007-9327/full/v30/i9/1018.htm

  Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. […] The role of Immunotherapy is emerging and offers improved survival for irresectable hilar cholangiocarcinoma. […] The causes of hCCA remain obscure in many patients. […] The estimated lifetime incidence of CCA with primary sclerosing cholangitis (PSC) ranges up to 20%. […] While PSC is a known risk factor for CCA, it is attributed to no more than 10% of CCA cases. […] Hepatobiliary flukes, specifically Opisthorchis viverrini and Clonorchis sinensis have been linked to the development of CCA in Southeast Asia, regardless of site. […] The presence of hepatitis B virus (commonly known as HBV) and hepatitis C virus (commonly known as HCV) has been linked to an increased risk of developing iCC. […] Studies do not confirm the association of HBV or HCV with hCCA.

• #53

  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. […] The Notch signaling pathway regulates embryonic development and proliferation of the biliary tree. […] Notch dysregulation has also been implicated in cholangiocarcinogenesis. […] Another evolutionary conserved, developmental pathway is the Hedgehog signaling pathway. […] Wnt signaling is also required for intrahepatic bile duct development and proliferation. […] The tumor stroma promotes tumor progression, via reciprocal communication between the stromal cells and cancer cells. […] 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 combination of DNA damage, evasion of apoptosis, and cell proliferation are all components of cell transformation. […] Further studies are necessary to elucidate the role of genetic aberrations, particularly in regions encoding key components of signaling pathways.

• #54 Cholangiocarcinoma pathogenesis: Role of the tumor microenvironment – Leyva-Illades – Translational Gastrointestinal Cancer

  https://tgc.amegroups.com/article/view/76/68

  Targeting the molecular signals released by these cells, in addition to strategies to suppress cholangiocarcinoma cell proliferation, could aid in cholangiocarcinoma treatment. […] Recent studies have shown that myofibroblast-derived platelet-derived growth factor protects cholangiocarcinoma cells from TRAIL-induced cell death via a hedgehog dependent mechanism in vitro and in vivo. […] Cholangiocarcinoma cells are known to overproduce many inflammatory cytokines, however, IL-6 is the most studied to date. […] Collectively, these data support the hypothesis that TAMs may play a role in cholangiocarcinoma progression. […] In summary, the research discussed in the present review highlights the role that the tumor microenvironment plays in the growth, progression, and metastatic invasion of cholangiocarcinoma.

• #55 Asian multicenter prospective study (CHOICE study) to elucidate the pathogenesis of cholangiocarcinoma(including FGFR2-rearranged) launched | National Cancer Center Japan

  https://www.ncc.go.jp/en/information/press_release/2022/1208/index.html

  A global study aiming at elucidating the pathogenesis of fibroblast growth factor receptor (FGFR) 2-rearranged cholangiocarcinoma is launched in Asian countries. […] Data on patients with biliary tract cancer will be collected not only from Japan but also from many other Asian countries to elucidate its pathogenesis. […] The study will analyze the genetic information, together with clinical information such as treatment and prognosis to help figure out the pathogenesis, contributing to the development of therapeutics. […] The development of therapeutics targeting the FGFR2 fusion gene, one of the target molecules, is ongoing mainly in Europe, the US, and Japan. […] More studies are needed to elucidate the genetic background of the majority of patients with biliary tract cancer. […] The CHOICE study will collect data on patients with cholangiocarcinoma classified as a rare cancer not only in Japan but also in many other Asian countries, contributing to the elucidation of its pathogenesis.

• #56 Asian multicenter prospective study (CHOICE study) to elucidate the pathogenesis of cholangiocarcinoma(including FGFR2-rearranged) launched | National Cancer Center Japan

  https://www.ncc.go.jp/en/information/press_release/2022/1208/index.html

  Genetic analysis results and the clinical information of the patient will be pooled for analysis to determine the frequency of FGFR2 fusion genes and encourage the development of therapeutics using molecular target drugs. […] The study findings may lead to the accumulation of useful data for developing novel drugs and expanding the market for existing molecular target drugs.

• #57

  https://journals.lww.com/international-journal-of-surgery/fulltext/2025/02000/current_advance_in_comprehensive_management_of.41.aspx

  The emergence of novel technologies undergo surgery is imminent. […] NIR-II fluorescence imaging has become a prevalent choice owing to its appealing advantages like deep penetration depth, high signal-to-background ratio. […] ICG is a heptamethine cyanine fluorophore that displays NIR fluorescence, and the first fluorophore clinically approved. […] The advent of SpyGlass cholangioscopy with high resolution images of the bile duct expected to provide a role in the tumor precise localization, which may guide the surgical plan. […] PDT plays an important role in the treatment of microvascular diseases and superficial tumors with its features of good tissue selectivity and few systemic side effects. […] NIR-PIT with its high selectivity, non-ionization, and immunogenicity, provides new ideas for cancer treatment. […] Understanding the tumor microenvironment change mechanism and early diagnosis by RNA or peptides should value in clinical practice.

• #58

  https://journals.lww.com/international-journal-of-surgery/fulltext/2025/02000/current_advance_in_comprehensive_management_of.41.aspx

  The emergence of novel technologies undergo surgery is imminent. […] NIR-II fluorescence imaging has become a prevalent choice owing to its appealing advantages like deep penetration depth, high signal-to-background ratio. […] ICG is a heptamethine cyanine fluorophore that displays NIR fluorescence, and the first fluorophore clinically approved. […] The advent of SpyGlass cholangioscopy with high resolution images of the bile duct expected to provide a role in the tumor precise localization, which may guide the surgical plan. […] PDT plays an important role in the treatment of microvascular diseases and superficial tumors with its features of good tissue selectivity and few systemic side effects. […] NIR-PIT with its high selectivity, non-ionization, and immunogenicity, provides new ideas for cancer treatment. […] Understanding the tumor microenvironment change mechanism and early diagnosis by RNA or peptides should value in clinical practice.

• #59 Application and mechanism of anticancer peptides in organoid models of intrahepatic cholangiocarcinoma | bioRxiv

  https://www.biorxiv.org/content/10.1101/2025.02.17.638575v1

  Background The clinical manifestations of intrahepatic cholangiocarcinoma (ICC) are non-specific, and only a small number of patients are eligible for surgical resection at the time of diagnosis, limiting treatment options. Anticancer peptides (ACPs) exhibit strong inhibitory activity against tumour cell lines, exhibit minimal side effects, are easily modified and optimised, and have low production costs. These attributes make ACPs a prospect for clinical applications. Simultaneously, the development of patient-derived three-dimensional organoids as a novel disease model has enabled the replication of the structure and heterogeneity of solid tumours. These organoids provide valuable tools for understanding disease mechanisms, conducting drug sensitivity tests, and developing targeted therapies.

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