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. […] 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.

• #2 Cholangiocarcinoma | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-021-00300-2

  Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. […] In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. […] Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. […] CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. […] Inflammation and progression of cholangiocarcinoma: role of angiogenic and lymphangiogenic mechanisms.

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

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

  Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. […] Considering the high heterogeneity of CCAs, individual characterization of these tumours at the genomic, epigenetic and molecular levels is an indispensable approach to ascertain their pathogenesis, paving the path for new therapeutic options and personalized medicine.

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

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

  The three subtypes of CCA can have different risk factors, pathobiology, clinical presentations, management and prognosis, as well as distinct epidemiological trends. […] iCCA can show three main patterns of growth: mass-forming, periductal-infiltrating, and intraductal-growing. […] CCA can be preceded by pre-invasive lesions. Histologically, although the vast majority of pCCA and dCCA are conventional mucin-producing adenocarcinomas or papillary tumours, iCCA shows several histological variants. […] Remarkably, the histological subtyping parallels the high molecular heterogeneity of CCAs and can be ascribed to different cells of origin and pathogenesis. […] 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.

• #6 Cholangiocarcinoma: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/277393-overview

  Cholangiocarcinomas arise from the intrahepatic or extrahepatic biliary epithelium. More than 90% are adenocarcinomas, and the remainder are squamous cell tumors. The etiology of most bile duct cancers remains undetermined. Long-standing inflammation, as with primary sclerosing cholangitis (PSC) or chronic parasitic infection, has been suggested to play a role by inducing hyperplasia, cellular proliferation, and, ultimately, malignant transformation. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative colitis and chronic cholecystitis. […] Cholangiocarcinomas tend to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes. Local extension occurs into the liver, porta hepatis, and regional lymph nodes of the celiac and pancreaticoduodenal chains. Life-threatening infection (cholangitis) may occur that requires immediate antibiotic intervention and aggressive biliary drainage.

• #7 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. […] 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.

• #8 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.

• #9 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.

• #10 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.

• #11 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. […] 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.

• #12 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.

• #13 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.

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

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

  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. […] The process of cholangiocarcinogenesis, and further tumour evolution and growth, involves complex and heterogeneous processes that include the interplay of extracellular ligands (such as pro-inflammatory cytokines, growth factors and bile acids, among others), 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.

• #15 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.

• #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 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.

• #17 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.

• #18 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.

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

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

  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. […] 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 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. […] In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

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

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

  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. […] 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 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. […] In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

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

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

  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. […] 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 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. […] In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

• #22 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.

• #23 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.

• #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 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. […] 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.

• #25 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 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. […] 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.

• #26 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.

• #27 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.

• #28 Cholangiocarcinoma | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-021-00300-2

  Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. […] In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. […] Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. […] CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. […] Inflammation and progression of cholangiocarcinoma: role of angiogenic and lymphangiogenic mechanisms.

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

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

  Chronic inflammation and fibrosis facilitate cholangiocyte transformation in a multistep manner, providing extracellular ligands that modulate several signalling pathways. […] CCA often arises in the setting of prolonged biliary inflammation and/or cholestasis, which contribute to carcinogenesis. […] The activation of these signalling pathways might also occur as a result of the interaction between the tumour epithelia and the tumour reactive stroma. […] The high heterogeneity and chemoresistance of CCAs represent a limitation for common therapeutic strategies, but it is a unique opportunity for personalized, targeted therapies.

• #30 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231024/Could-the-microbiome-hold-the-key-to-diagnosing-and-treating-biliary-tract-cancer.aspx

  Biliary tract cancer comprises a wide range of invasive adenocarcinomas, including gallbladder carcinoma and cholangiocarcinoma. Cholangiocarcinoma, often associated with a poor prognosis, can be further classified as intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma. […] Epidemiological studies have identified multiple risk factors associated with the incidence of cholangiocarcinoma. Some of these risk factors include hepatolithiasis, choledocholithiasis, primary sclerosing cholangitis, cholelithiasis, and bile duct cysts. […] Previous studies have observed a relationship between gut dysbiosis and the incidence of ICC, possibly due to the connection between gut microbiota, cytokine profiles, and bile acid. Patients with ICC exhibit significant – and -diversity as compared to patients with liver cirrhosis hepatocellular carcinoma and healthy individuals.

• #31 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231024/Could-the-microbiome-hold-the-key-to-diagnosing-and-treating-biliary-tract-cancer.aspx

  Genomic studies have indicated the presence of Streptococcus, Enterococcus, Bacteroides, Klebsiella, and Pyramidobacter within the biliary microflora. These bacteria play a significant role in the onset of cholangiocarcinoma; therefore, these microbes could be used as a biomarker for the condition. […] Prolonged inflammation plays a critical role in the development of gallbladder cancer, which also influences the biliary tract. The risk of gallbladder cancer increases in the presence of bacterial infections, which could induce chronic inflammation, carcinogenic toxin, and metabolite production. […] The liver-bile acid-microbiota axis plays a crucial role in gastrointestinal carcinogenesis. Thus, distinct changes in plasma bile acid concentrations could be used as potential diagnostic biomarkers to distinguish cholangiocarcinoma from benign biliary diseases and healthy individuals.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231024/Could-the-microbiome-hold-the-key-to-diagnosing-and-treating-biliary-tract-cancer.aspx

  Genomic studies have indicated the presence of Streptococcus, Enterococcus, Bacteroides, Klebsiella, and Pyramidobacter within the biliary microflora. These bacteria play a significant role in the onset of cholangiocarcinoma; therefore, these microbes could be used as a biomarker for the condition. […] Prolonged inflammation plays a critical role in the development of gallbladder cancer, which also influences the biliary tract. The risk of gallbladder cancer increases in the presence of bacterial infections, which could induce chronic inflammation, carcinogenic toxin, and metabolite production. […] The liver-bile acid-microbiota axis plays a crucial role in gastrointestinal carcinogenesis. Thus, distinct changes in plasma bile acid concentrations could be used as potential diagnostic biomarkers to distinguish cholangiocarcinoma from benign biliary diseases and healthy individuals.

• #33 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231024/Could-the-microbiome-hold-the-key-to-diagnosing-and-treating-biliary-tract-cancer.aspx

  Genomic studies have indicated the presence of Streptococcus, Enterococcus, Bacteroides, Klebsiella, and Pyramidobacter within the biliary microflora. These bacteria play a significant role in the onset of cholangiocarcinoma; therefore, these microbes could be used as a biomarker for the condition. […] Prolonged inflammation plays a critical role in the development of gallbladder cancer, which also influences the biliary tract. The risk of gallbladder cancer increases in the presence of bacterial infections, which could induce chronic inflammation, carcinogenic toxin, and metabolite production. […] The liver-bile acid-microbiota axis plays a crucial role in gastrointestinal carcinogenesis. Thus, distinct changes in plasma bile acid concentrations could be used as potential diagnostic biomarkers to distinguish cholangiocarcinoma from benign biliary diseases and healthy individuals.

• #34 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.

• #35 Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development

  https://www.mdpi.com/2072-6694/14/6/1442

  As previously discussed in the risk factor section, PSC patients are those presenting with the highest risk to develop CCA in Western countries. While the exact molecular mechanisms linking PSC to carcinogenesis are still not completely clarified, increased biliary IL-6 excretion during this disease may play a role. IL-6 production is, in fact, enhanced in PSC by the stimulation of biliary cells by autoantibodies or as part of senescence-associated secretory phenotype (SASP) excreted by senescent cells. […] The molecular mechanisms at the base of Type I (Todani classification) choledochal cysts formation are largely unanswered. Similarly, the reasons for the possible evolution of these lesions in CCA remain obscure. General inflammatory or proliferative and reactive processes were claimed to justify the possible carcinogenic evolution in Type I choledochal cysts, a form that alone represents the 80–90% of this class of diseases. […] In conclusion, while both O. viverrini and C. sinensis are classified as type I carcinogens, several molecular aspects remain to be identified in the progression from biliary infection to CCA.

• #36 Cholangiocarcinoma | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-021-00300-2

  Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. […] In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. […] Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. […] CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. […] Inflammation and progression of cholangiocarcinoma: role of angiogenic and lymphangiogenic mechanisms.

• #37 Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development

  https://www.mdpi.com/2072-6694/14/6/1442

  The identification of the carcinogenic mechanisms that lead well-recognized premalignant conditions to become CCA may have importance in this setting. In this review, we analyze the specific risk factors for CCA development to better understand the possible molecular events leading to cancer. […] Multiple mechanisms have been suggested to explain CCA onset following liver fluke infections. O. viverrini-mediated mechanical damage to the biliary tract is just the first general effect. Other factors, such as the activation of immune processes and parasite-secreted mitogenic molecules, play a role in CCA. For instance, O. viverrini-Granulin-1 (Ov-GRN-1), which has a similar sequence of mammalian granulin (an important growth factor likely to be involved in carcinogenesis and tumor spreading), was identified in the biliary epithelia of O. viverrini-infected hamsters.

• #38 Learn About Cholangiocarcinoma | Cholangiocarcinoma Foundation

  https://www.cholangiocarcinoma.org/learn-about-cholangiocarcinoma/

  Long term infection with either hepatitis B virus or hepatitis C virus increases the risk of intrahepatic cholangiocarcinoma. […] Cirrhosis is a condition in which the liver does not function properly due to long-term damage. […] Bile duct stones are similar to, but much smaller than gallstones, which can also cause inflammation that increases the risk of cholangiocarcinoma. […] These abnormalities can allow digestive juices from the pancreas to reflux (flow back upstream) into the bile ducts. […] Choledochal cysts are bile-filled sacs that are connected to the bile duct. […] A history of cholangiocarcinoma in the family seems to slightly increase a persons chances of developing this cancer, but the risk is still extremely low. […] Both conditions lead to chronic inflammation and/or changes in the intestinal microbiome and could lead to cholangiocarcinoma.

• #39

  https://link.springer.com/article/10.1007/s00535-013-0894-y

  The molecular pathogenesis of iCCA may have similarities with the pathogenesis of hepatocellular cancer because many of the dominant risk factors associated with HCC such as cirrhosis, HBV, HCV and metabolic syndrome are also risk factors for iCCA. […] Key molecular events involved in the pathogenesis of iCCA are summarized in Fig. 2. In the classical model of tumor pathogenesis, promotion of tumor development follows chronic biliary inflammation with the release of inflammatory mediators, and occurs in the setting of cholestasis, where bile acid signaling could promote cholangiocyte growth via activation of growth factors. […] The tumor stroma and local microenvironment play a crucial role in cancer progression and in therapeutic responses in many different cancers. A contribution of the stromal compartment to the pathogenesis of iCCA has also been recognized.

• #40

  https://scispace.com/papers/the-riglers-triad-a-case-of-gallstone-ileus-22gb1ce13m

  Gallstones seem to increase the risk of both intra- and extrahepatic cholangiocarcinoma, however, this risk seems to decline to the level of the background population with time after cholecystectomy.

• #41 Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations – Marcano-Bonilla – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/12259/html

  The progressive accumulation of oncogenic aberrations in the biliary epithelium induce malignant transformation. […] The fact that about 60% of GBC have intestinal metaplasia and more than 90% have dysplasia in the adjacent mucosa supports this hypothesis. […] The molecular pathogenesis of BTC is poorly understood. […] The main mechanism is through cholelithiasis, which leads to chronic cholecystitis and subsequent oncogenesis. […] Another mechanism implicated in GBC pathogenesis is the presence of an APBJ. […] The pathogenic mechanisms leading to development of CCA are also unclear. […] The resulting biliary damage generates cholestasis, which causes aberrant bile acid signaling. […] The progressive accumulation of oncogenic aberrations in the biliary epithelium induce malignant transformation.

• #42 Bile Duct Cancer (Cholangiocarcinoma) Causes & Risk Factors | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/bile-duct-cancer-cholangiocarcinoma/causes-risk-factors

  People who have chronic (long-standing) inflammation of the bile ducts have an increased risk of developing bile duct cancer. […] Other inflammatory conditions can increase the risk of developing bile duct cancer: […] Ulcerative colitis is an inflammation of the large intestine. It is often associated with inflammation of the bile ducts, which is called primary sclerosing cholangitis. […] Although rarely seen in the United States, food- or water-borne parasites that live in the bile ducts are common in Asia and raise the risk of developing bile duct cancer. […] Congenital bile duct cysts are typically diagnosed in childhood. The lining of these sacs often contains precancerous cells that increase the risk of developing cancer later in life. […] This inflammatory disease is a risk factor for cancer of the intrahepatic bile ducts. […] Studies have suggested that intrahepatic bile duct cancer is more common among heavy smokers. […] Bile duct cancer occurs most often in older people. […] Diabetes can slightly raise the risk for intrahepatic bile duct cancer.

• #43 Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development

  https://www.mdpi.com/2072-6694/14/6/1442

  As previously discussed in the risk factor section, PSC patients are those presenting with the highest risk to develop CCA in Western countries. While the exact molecular mechanisms linking PSC to carcinogenesis are still not completely clarified, increased biliary IL-6 excretion during this disease may play a role. IL-6 production is, in fact, enhanced in PSC by the stimulation of biliary cells by autoantibodies or as part of senescence-associated secretory phenotype (SASP) excreted by senescent cells. […] The molecular mechanisms at the base of Type I (Todani classification) choledochal cysts formation are largely unanswered. Similarly, the reasons for the possible evolution of these lesions in CCA remain obscure. General inflammatory or proliferative and reactive processes were claimed to justify the possible carcinogenic evolution in Type I choledochal cysts, a form that alone represents the 80–90% of this class of diseases. […] In conclusion, while both O. viverrini and C. sinensis are classified as type I carcinogens, several molecular aspects remain to be identified in the progression from biliary infection to CCA.

• #44 Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations – Marcano-Bonilla – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/12259/html

  The progressive accumulation of oncogenic aberrations in the biliary epithelium induce malignant transformation. […] The fact that about 60% of GBC have intestinal metaplasia and more than 90% have dysplasia in the adjacent mucosa supports this hypothesis. […] The molecular pathogenesis of BTC is poorly understood. […] The main mechanism is through cholelithiasis, which leads to chronic cholecystitis and subsequent oncogenesis. […] Another mechanism implicated in GBC pathogenesis is the presence of an APBJ. […] The pathogenic mechanisms leading to development of CCA are also unclear. […] The resulting biliary damage generates cholestasis, which causes aberrant bile acid signaling. […] The progressive accumulation of oncogenic aberrations in the biliary epithelium induce malignant transformation.

• #45 Learn About Cholangiocarcinoma | Cholangiocarcinoma Foundation

  https://www.cholangiocarcinoma.org/learn-about-cholangiocarcinoma/

  Long term infection with either hepatitis B virus or hepatitis C virus increases the risk of intrahepatic cholangiocarcinoma. […] Cirrhosis is a condition in which the liver does not function properly due to long-term damage. […] Bile duct stones are similar to, but much smaller than gallstones, which can also cause inflammation that increases the risk of cholangiocarcinoma. […] These abnormalities can allow digestive juices from the pancreas to reflux (flow back upstream) into the bile ducts. […] Choledochal cysts are bile-filled sacs that are connected to the bile duct. […] A history of cholangiocarcinoma in the family seems to slightly increase a persons chances of developing this cancer, but the risk is still extremely low. […] Both conditions lead to chronic inflammation and/or changes in the intestinal microbiome and could lead to cholangiocarcinoma.

• #46 Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations – Marcano-Bonilla – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/12259/html

  Biliary tract cancers (BTC) are malignancies that arise from the epithelium of the biliary system and comprise the second most common type of hepatobiliary cancer worldwide. […] The risk factors most strongly associated with BTC are those characterized by chronic inflammatory states, such as primary sclerosing cholangitis (PSC), chronic biliary tract infection, asymptomatic stone disease, and diabetes mellitus, among others. […] Thus, BTC, similar to most other cancers, is a complex disease resulting from the combination of familial genetic predisposition and certain environmental factors. […] The mechanisms by which such SNP variations influence the pathogenesis of BTC are poorly understood. […] The pathogenic mechanisms leading to development of CCA are also unclear. […] The resulting biliary damage generates cholestasis, which causes aberrant bile acid signaling.

• #47 Learn About Cholangiocarcinoma | Cholangiocarcinoma Foundation

  https://www.cholangiocarcinoma.org/learn-about-cholangiocarcinoma/

  Long term infection with either hepatitis B virus or hepatitis C virus increases the risk of intrahepatic cholangiocarcinoma. […] Cirrhosis is a condition in which the liver does not function properly due to long-term damage. […] Bile duct stones are similar to, but much smaller than gallstones, which can also cause inflammation that increases the risk of cholangiocarcinoma. […] These abnormalities can allow digestive juices from the pancreas to reflux (flow back upstream) into the bile ducts. […] Choledochal cysts are bile-filled sacs that are connected to the bile duct. […] A history of cholangiocarcinoma in the family seems to slightly increase a persons chances of developing this cancer, but the risk is still extremely low. […] Both conditions lead to chronic inflammation and/or changes in the intestinal microbiome and could lead to cholangiocarcinoma.

• #48 Learn About Cholangiocarcinoma | Cholangiocarcinoma Foundation

  https://www.cholangiocarcinoma.org/learn-about-cholangiocarcinoma/

  A radioactive substance called Thorotrast (thorium dioxide) was used as a contrast agent for x-rays until the 1950s and can lead to cholangiocarcinoma, as well as to some types of liver cancer. […] Studies have found that several other risk factors may increase the risk of cholangiocarcinoma, but the link between these risk factors and cholangiocarcinoma is not as clear.

• #49 Cholangiocarcinoma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/cholangiocarcinoma/

  Several non-genetic risk factors for cholangiocarcinoma have been identified. These include a bile duct disease called primary sclerosing cholangitis, bile duct stones or cysts, and exposure to certain chemical toxins used in manufacturing. In Southeast Asia, infection with parasitic worms that live in the human bile ducts greatly increase the risk of developing cholangiocarcinoma. Other risk factors that have been studied include long-term infection with viral hepatitis B or C, scarring of the liver (cirrhosis), and chronic diseases such as inflammatory bowel disease and diabetes. Researchers suspect that certain lifestyle factors, including smoking, alcohol use, and obesity, may also contribute to the risk of developing cholangiocarcinoma. […] Studies suggest that a combination of genetic, environmental, and lifestyle factors influence whether a person will develop cholangiocarcinoma. However, most people who develop the disease do not have any of the identified risk factors.

• #50 Bile Duct Cancer (Cholangiocarcinoma) Causes & Risk Factors | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/bile-duct-cancer-cholangiocarcinoma/causes-risk-factors

  People who have chronic (long-standing) inflammation of the bile ducts have an increased risk of developing bile duct cancer. […] Other inflammatory conditions can increase the risk of developing bile duct cancer: […] Ulcerative colitis is an inflammation of the large intestine. It is often associated with inflammation of the bile ducts, which is called primary sclerosing cholangitis. […] Although rarely seen in the United States, food- or water-borne parasites that live in the bile ducts are common in Asia and raise the risk of developing bile duct cancer. […] Congenital bile duct cysts are typically diagnosed in childhood. The lining of these sacs often contains precancerous cells that increase the risk of developing cancer later in life. […] This inflammatory disease is a risk factor for cancer of the intrahepatic bile ducts. […] Studies have suggested that intrahepatic bile duct cancer is more common among heavy smokers. […] Bile duct cancer occurs most often in older people. […] Diabetes can slightly raise the risk for intrahepatic bile duct cancer.

• #51 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.

• #52 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 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. […] 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.

• #53 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

  For patients with cholangiocarcinoma, or bile duct cancer, the first line of treatment often includes standard cancer treatments, such as surgery, chemotherapy and radiation therapy. […] FGFR inhibitors, in combination with standard treatments, have extended the lives of many with this disease. […] 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. […] These new treatments highlight the need to better understand each patients cancer genetics at different points in time.

• #54 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

  For patients with cholangiocarcinoma, or bile duct cancer, the first line of treatment often includes standard cancer treatments, such as surgery, chemotherapy and radiation therapy. […] FGFR inhibitors, in combination with standard treatments, have extended the lives of many with this disease. […] 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. […] These new treatments highlight the need to better understand each patients cancer genetics at different points in time.

• #55 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

  For patients with cholangiocarcinoma, or bile duct cancer, the first line of treatment often includes standard cancer treatments, such as surgery, chemotherapy and radiation therapy. […] FGFR inhibitors, in combination with standard treatments, have extended the lives of many with this disease. […] 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. […] These new treatments highlight the need to better understand each patients cancer genetics at different points in time.

• #56 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 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. […] 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.

• #57 Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

  https://www.mdpi.com/2072-6694/16/4/801

  The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. […] The molecular pathobiology of CCA has been extensively studied in depth in recent years, leading to the development of therapies that have shown promise for treatment and the emergence of FDA-approved drugs. Despite the significant advances in the field of CCA, there is still much work to identify other novel targets and optimize the efficacies of existing therapies. With continued research and clinical efforts, the goal is to improve the prognosis and quality of life for patients with CCA.

• #58 Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

  https://www.mdpi.com/2072-6694/16/4/801

  The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. […] The molecular pathobiology of CCA has been extensively studied in depth in recent years, leading to the development of therapies that have shown promise for treatment and the emergence of FDA-approved drugs. Despite the significant advances in the field of CCA, there is still much work to identify other novel targets and optimize the efficacies of existing therapies. With continued research and clinical efforts, the goal is to improve the prognosis and quality of life for patients with CCA.

• #59 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.

• #60 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.

• #61 Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

  https://www.mdpi.com/2072-6694/16/4/801

  Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). The molecular pathogenesis of CCA is complex and multifactorial. A multitude of molecular mechanisms have been implicated in the process of cholangio-carcinogenesis and may differ by anatomical location and etiology. The tumor cells undergo diverse genetic and epigenetic alterations resulting in enhanced proliferation signaling, dysregulation of apoptosis, angiogenesis, invasion, and stromal proliferation. Prolonged biliary inflammation, cholestasis, and fibrosis incite aberrant activation of various receptors and deregulate intracellular signaling pathways. Advances in pathology, molecular biology, and genetics have led to an improved understanding of the molecular mechanisms underlying CCA development. This enables the identification of specific molecular targets and prediction of treatment responses for more efficacious interventions. The complex tumor microenvironment comprising a diverse array of tumor cells, highly invasive behavior, desmoplastic and hypovascular stroma, mutational landscape, development of therapeutic resistance, and intra and inter-tumoral heterogeneity has led to refractoriness to chemotherapy. Nearly half of the CCAs have targetable mutations. This review will summarize the risk factors, current evidence about the pathophysiology and molecular genetics, along with potential role of liquid biopsy in diagnostics. It will also highlight the current and emerging treatment options, advances in the field of personalized medicine, the role of novel compounds from natural sources, and the therapeutic implications of modulation of gut microbiota to reverse microbial dysbiosis. Through our comprehensive summary of the molecular mechanisms underlying CCA and the recent therapeutic advances in this field, our review aims to contribute to a better understanding of CCA and to highlight existing and upcoming potential therapeutic options for patients with CCA.

• #62 Finding a rare bile duct cancer’s weaknesses | Fred Hutchinson Cancer Center

  https://www.fredhutch.org/en/news/center-news/2024/07/boila-kugel-dod-ccf-icc.html

  Cholangiocarcinoma, or CCA, is cancer of the bile ducts. ICC is intra-hepatic or intra-liver CCA. It arises in the bile ducts within the liver and makes up about 10-20% of all cases of CCA. […] A deeper understanding of this subtypes genetic underpinnings and potential drug susceptibilities will lay the groundwork, Boila hopes, for clinical trials of new, more tailored treatments for ICC. […] About 20% of human ICC cases have a mutation in the ARID1A gene. ARID1A is part of a protein complex that restructures DNA packaging to influence expression of certain genes. Its loss may shift which genes are turned on or off in a way that promotes tumor formation. Boilas DOD funding will allow him to begin untangling this mechanism. […] Using this ARID1A-knockout model, well be able to gather data showing the driving factors promoting ICC in ARID1A-mutated bile duct cells, Boila said. Were trying to find the mechanisms that regulate tumor formation in this ICC subtype.

• #63 Finding a rare bile duct cancer’s weaknesses | Fred Hutchinson Cancer Center

  https://www.fredhutch.org/en/news/center-news/2024/07/boila-kugel-dod-ccf-icc.html

  Cholangiocarcinoma, or CCA, is cancer of the bile ducts. ICC is intra-hepatic or intra-liver CCA. It arises in the bile ducts within the liver and makes up about 10-20% of all cases of CCA. […] A deeper understanding of this subtypes genetic underpinnings and potential drug susceptibilities will lay the groundwork, Boila hopes, for clinical trials of new, more tailored treatments for ICC. […] About 20% of human ICC cases have a mutation in the ARID1A gene. ARID1A is part of a protein complex that restructures DNA packaging to influence expression of certain genes. Its loss may shift which genes are turned on or off in a way that promotes tumor formation. Boilas DOD funding will allow him to begin untangling this mechanism. […] Using this ARID1A-knockout model, well be able to gather data showing the driving factors promoting ICC in ARID1A-mutated bile duct cells, Boila said. Were trying to find the mechanisms that regulate tumor formation in this ICC subtype.

• #64 Finding a rare bile duct cancer’s weaknesses | Fred Hutchinson Cancer Center

  https://www.fredhutch.org/en/news/center-news/2024/07/boila-kugel-dod-ccf-icc.html

  Boilas CCF award will allow him to better understand another ICC subtype, driven by mutations in a gene involved in metabolism. This gene encodes the enzyme isocitrate dehydrogenase, or IDH, which creates an important metabolite in our cells energy-generating cycle. […] Tumor cells tend to be less differentiated than normal cells, which means they cant perform the specialized functions that are unique to various cell types. The gene expression shifts in IDH1-mutant cells help promote cancer by blocking the liver stem cells ability to differentiate into functional liver cells. […] Boila will work to better understand the critical role that PP2A plays in IDH1-mutant ICC biology, and how modifying PP2A function may influence tumor cell growth, survival and drug sensitivities.

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

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

  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. […] 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 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. […] In summary, there is a complex net of different factors and pathways involved in CCA development, growth, and propagation.

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

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

  Chronic inflammation and fibrosis facilitate cholangiocyte transformation in a multistep manner, providing extracellular ligands that modulate several signalling pathways. […] CCA often arises in the setting of prolonged biliary inflammation and/or cholestasis, which contribute to carcinogenesis. […] The activation of these signalling pathways might also occur as a result of the interaction between the tumour epithelia and the tumour reactive stroma. […] The high heterogeneity and chemoresistance of CCAs represent a limitation for common therapeutic strategies, but it is a unique opportunity for personalized, targeted therapies.

• #67 Cholangiocarcinoma – Bile Duct Cancer – anyone else dealing with this? | Mayo Clinic Connect

  https://connect.mayoclinic.org/discussion/cholangiocarcinoma-bile-duct-cancer-anyone-else-dealing-with-this/?pg=20

  After many call we have found that it is non small cell carcinoma on the liver duct (cholangiocarcinoma). Very fatal and rare. […] „In the last several years there have been significant new insights into the molecular pathogenesis of CCA. New diagnostic and therapeutic modalities have also been developed, resulting in improved detection rates and outcomes. In addition, we have now entered the era of targeted therapies for human cancers.” […] Annual CT scan that surveils stable pleural placque in lungs from asbestos exposure 50 years ago detected a 5 cm lesion on liver. Follow on MRI confirmed diagnosis of cholangiocarcinoma.

• #68 Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

  https://www.mdpi.com/2072-6694/16/4/801

  The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. […] The molecular pathobiology of CCA has been extensively studied in depth in recent years, leading to the development of therapies that have shown promise for treatment and the emergence of FDA-approved drugs. Despite the significant advances in the field of CCA, there is still much work to identify other novel targets and optimize the efficacies of existing therapies. With continued research and clinical efforts, the goal is to improve the prognosis and quality of life for patients with CCA.

• #69 Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches

  https://www.mdpi.com/2072-6694/16/4/801

  The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. […] The molecular pathobiology of CCA has been extensively studied in depth in recent years, leading to the development of therapies that have shown promise for treatment and the emergence of FDA-approved drugs. Despite the significant advances in the field of CCA, there is still much work to identify other novel targets and optimize the efficacies of existing therapies. With continued research and clinical efforts, the goal is to improve the prognosis and quality of life for patients with CCA.

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