Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (C... more Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. Methods: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. Results: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups...
Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits... more Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.
BACKGROUND & AIMS-Macrophages contribute to liver disease, but their role in cholestatic liver in... more BACKGROUND & AIMS-Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. METHODS-Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the IAP antagonist BV6) and chronic (Mdr2 −/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from PSC patients. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2 −/− mice) were determined in BV6-injected mice.
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cho... more Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome se...
Purpose of review-The only currently approved treatment for primary sclerosing cholangitis (PSC) ... more Purpose of review-The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12-18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein. Recent findings-Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations. Summary-Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.
This is the author manuscript accepted for publication and has undergone full peer review but has... more This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version record. Please cite this article as
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secr... more Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis. Using a co-culture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a PDGF-dependent manner. We also identified Bcl-xL as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also upregulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule BH3 mimetic A-1331852 or Bcl-xL-specific siRNA induced apoptosis in PDGF-activated fibroblasts but not in quiesc...
Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. S... more Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions such as primary sclerosing cholangitis (PSC) are risk factors. Non-invasive differential diagnosis between intrahepatic CCA (iCCA) and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate non-invasive biomarkers for PSC, CCA or HCC are not available. In the search of novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n=43), PSC (n=30) or HCC (n=29) patients, and healthy individuals (control, n=32), and their protein content was characterized. By using nanoparticle tracking analysis (NTA), serum EV concentration was found higher in HCC than all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by NTA) and markers (CD9, CD63 and CD81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among g...
Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile duc... more Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation, and are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2 years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis have better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged including potential driver FGFR gene fusions and somatic mutations in IDH 1/2 in iCCA, PRKACA or PRKACB gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, potentially actionable molecular aberrations in each CCA subtype, and role of immunotherapy in CCA.
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options... more Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options. Keywords cholangiocarcinoma; molecular pathogenesis; targeted therapy Cholangiocarcinoma (CCA) is the most common primary biliary malignancy and accounts for 3% of all gastrointestinal malignances. 1 Cholangiocarcinomas arise from varying locations within the biliary tree, and are classified according to their anatomic origin into intrahepatic, perihilar, and distal cholangiocarcinoma. The second-order bile ducts are the anatomical boundary between intrahepatic CCA (iCCA) and perihilar CCA (pCCA), whereas the cystic duct is the point of distinction between pCCA and distal CCA (dCCA). Although these subtypes exhibit extensive desmoplasia and markers of cholangiocyte differentiation, each has a unique cancer biology and distinct therapeutic options. 1
It has become increasingly apparent of late that inflammation plays an integral role in a spectru... more It has become increasingly apparent of late that inflammation plays an integral role in a spectrum of malignancies including cholangiocarcinoma (CCA). Primary sclerosing cholangitis with chronic inflammation is the most common risk factor for CCA in the Western world. Recent work has highlighted that inflammatory pathways are essential in carcinogenesis and tissue invasion and migration. Inflammation advances carcinogenesis by induction of DNA damage, evasion of apoptosis, promotion of cell proliferation, and neoangiogenesis. CCA is characterized by the presence of a desmoplastic stroma consisting of cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating lymphocytes. This rich inflammatory milieu is vital to the cancer ecosystem, and targeting its components represents an attractive therapeutic option.
Liver transplantation following high dose neoadjuvant radiotherapy with chemosensitization achiev... more Liver transplantation following high dose neoadjuvant radiotherapy with chemosensitization achieves excellent results for patients with early stage, unresectable hilar cholangiocarcinoma or cholangiocarcinoma arising in the setting of primary sclerosing cholangitis.
The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolis... more The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xLand Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded...
Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and ... more Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and poor outcomes. Specifi c diagnostic and therapeutic approaches are undertaken for cholangiocarcinomas of diff erent anatomical locations (intrahepatic, perihilar, and distal). Mixed hepatocellular cholangiocarcinomas have emerged as a distinct subtype of primary liver cancer. Clinicians need to be aware of intrahepatic cholangiocarcinomas arising in cirrhosis and properly assess liver masses in this setting for cholangiocarcinoma. Management of biliary obstruction is obligatory in perihilar cholangiocarcinoma, and advanced cytological tests such as fl uorescence in-situ hybridisation for aneusomy are helpful in the diagnosis. Liver transplantation is a curative option for selected patients with perihilar but not with intrahepatic or distal cholangiocarcinoma. International eff orts of clinicians and scientists are helping to identify the genetic drivers of cholangiocarcinoma progression, which will unveil early diagnostic markers and direct development of individualised therapies.
A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Ou... more A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Our laboratory has reported that following apoptosis human intrahepatic biliary epithelial cells (HiBEC) translocate the E2 subunit of the pyruvate dehydrogenase complex immunologically intact into apoptotic bodies, forming an apotope. However, the cell type and specificity of this reaction has not been fully defined. To address this issue we have investigated whether PDC-E2, BCOADC-E2, OGDC-E2, four additional inner mitochondrial enzymes and four nuclear antigens remain immunologically intact with respect to post-apoptotic translocation in HiBEC and 3 additional control epithelial cells. We report that all three 2-oxo acid dehydrogenase enzymes share the ability to remain intact within the apotope of HiBEC. Interestingly the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex also remained intact in the other cell types tested. We extended the data using 95 AMA + and 19 AMA-PBC and 76 control sera for reactivity against the 7 mitochondrial proteins studied herein and also the ability of AMAsera to react with HIBEC apotopes. Sera from 3/95 AMA + sera, but none of the controls, reacted with 2, 4-dienoyl
Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (C... more Background: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. Methods: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. Results: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups...
Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits... more Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.
BACKGROUND & AIMS-Macrophages contribute to liver disease, but their role in cholestatic liver in... more BACKGROUND & AIMS-Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. METHODS-Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the IAP antagonist BV6) and chronic (Mdr2 −/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from PSC patients. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2 −/− mice) were determined in BV6-injected mice.
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cho... more Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome se...
Purpose of review-The only currently approved treatment for primary sclerosing cholangitis (PSC) ... more Purpose of review-The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12-18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein. Recent findings-Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations. Summary-Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.
This is the author manuscript accepted for publication and has undergone full peer review but has... more This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version record. Please cite this article as
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secr... more Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis. Using a co-culture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a PDGF-dependent manner. We also identified Bcl-xL as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also upregulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule BH3 mimetic A-1331852 or Bcl-xL-specific siRNA induced apoptosis in PDGF-activated fibroblasts but not in quiesc...
Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. S... more Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions such as primary sclerosing cholangitis (PSC) are risk factors. Non-invasive differential diagnosis between intrahepatic CCA (iCCA) and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate non-invasive biomarkers for PSC, CCA or HCC are not available. In the search of novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n=43), PSC (n=30) or HCC (n=29) patients, and healthy individuals (control, n=32), and their protein content was characterized. By using nanoparticle tracking analysis (NTA), serum EV concentration was found higher in HCC than all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by NTA) and markers (CD9, CD63 and CD81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among g...
Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile duc... more Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation, and are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2 years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis have better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged including potential driver FGFR gene fusions and somatic mutations in IDH 1/2 in iCCA, PRKACA or PRKACB gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, potentially actionable molecular aberrations in each CCA subtype, and role of immunotherapy in CCA.
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options... more Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options. Keywords cholangiocarcinoma; molecular pathogenesis; targeted therapy Cholangiocarcinoma (CCA) is the most common primary biliary malignancy and accounts for 3% of all gastrointestinal malignances. 1 Cholangiocarcinomas arise from varying locations within the biliary tree, and are classified according to their anatomic origin into intrahepatic, perihilar, and distal cholangiocarcinoma. The second-order bile ducts are the anatomical boundary between intrahepatic CCA (iCCA) and perihilar CCA (pCCA), whereas the cystic duct is the point of distinction between pCCA and distal CCA (dCCA). Although these subtypes exhibit extensive desmoplasia and markers of cholangiocyte differentiation, each has a unique cancer biology and distinct therapeutic options. 1
It has become increasingly apparent of late that inflammation plays an integral role in a spectru... more It has become increasingly apparent of late that inflammation plays an integral role in a spectrum of malignancies including cholangiocarcinoma (CCA). Primary sclerosing cholangitis with chronic inflammation is the most common risk factor for CCA in the Western world. Recent work has highlighted that inflammatory pathways are essential in carcinogenesis and tissue invasion and migration. Inflammation advances carcinogenesis by induction of DNA damage, evasion of apoptosis, promotion of cell proliferation, and neoangiogenesis. CCA is characterized by the presence of a desmoplastic stroma consisting of cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating lymphocytes. This rich inflammatory milieu is vital to the cancer ecosystem, and targeting its components represents an attractive therapeutic option.
Liver transplantation following high dose neoadjuvant radiotherapy with chemosensitization achiev... more Liver transplantation following high dose neoadjuvant radiotherapy with chemosensitization achieves excellent results for patients with early stage, unresectable hilar cholangiocarcinoma or cholangiocarcinoma arising in the setting of primary sclerosing cholangitis.
The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolis... more The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xLand Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded...
Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and ... more Cholangiocarcinoma represents a diverse group of epithelial cancers united by late diagnosis and poor outcomes. Specifi c diagnostic and therapeutic approaches are undertaken for cholangiocarcinomas of diff erent anatomical locations (intrahepatic, perihilar, and distal). Mixed hepatocellular cholangiocarcinomas have emerged as a distinct subtype of primary liver cancer. Clinicians need to be aware of intrahepatic cholangiocarcinomas arising in cirrhosis and properly assess liver masses in this setting for cholangiocarcinoma. Management of biliary obstruction is obligatory in perihilar cholangiocarcinoma, and advanced cytological tests such as fl uorescence in-situ hybridisation for aneusomy are helpful in the diagnosis. Liver transplantation is a curative option for selected patients with perihilar but not with intrahepatic or distal cholangiocarcinoma. International eff orts of clinicians and scientists are helping to identify the genetic drivers of cholangiocarcinoma progression, which will unveil early diagnostic markers and direct development of individualised therapies.
A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Ou... more A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Our laboratory has reported that following apoptosis human intrahepatic biliary epithelial cells (HiBEC) translocate the E2 subunit of the pyruvate dehydrogenase complex immunologically intact into apoptotic bodies, forming an apotope. However, the cell type and specificity of this reaction has not been fully defined. To address this issue we have investigated whether PDC-E2, BCOADC-E2, OGDC-E2, four additional inner mitochondrial enzymes and four nuclear antigens remain immunologically intact with respect to post-apoptotic translocation in HiBEC and 3 additional control epithelial cells. We report that all three 2-oxo acid dehydrogenase enzymes share the ability to remain intact within the apotope of HiBEC. Interestingly the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex also remained intact in the other cell types tested. We extended the data using 95 AMA + and 19 AMA-PBC and 76 control sera for reactivity against the 7 mitochondrial proteins studied herein and also the ability of AMAsera to react with HIBEC apotopes. Sera from 3/95 AMA + sera, but none of the controls, reacted with 2, 4-dienoyl
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