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6. Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Author

Banales, J.M., Marin, J.J.G., LaMarca, A., Rodrigues, P.M., Khan, S.A., Roberts, L.R., Cardinale, V., Carpino, G., Andersen, J.B., Braconi, C., Calvisi, D.F., Perugorria, M.J., Fabris, L., Boulter, L, Macias, R.I.R., Gaudio, E., Alvaro, D., Gradilone, S.A., Strazzabosco, M, Marzioni, M., Coulouarn, C., Fouassier, L., Raggi, C., Invernizzi, P, Mertens, J.C., Moncsek, A., Rizvi, S., Heimbach, J., Groot Koerkamp, B. (Bas), Bruix, J. (J.), Forner, A., Bridgewater, J., Valle, J.W., Gores, G.J. (Gregory), Banales, J.M., Marin, J.J.G., LaMarca, A., Rodrigues, P.M., Khan, S.A., Roberts, L.R., Cardinale, V., Carpino, G., Andersen, J.B., Braconi, C., Calvisi, D.F., Perugorria, M.J., Fabris, L., Boulter, L, Macias, R.I.R., Gaudio, E., Alvaro, D., Gradilone, S.A., Strazzabosco, M, Marzioni, M., Coulouarn, C., Fouassier, L., Raggi, C., Invernizzi, P, Mertens, J.C., Moncsek, A., Rizvi, S., Heimbach, J., Groot Koerkamp, B. (Bas), Bruix, J. (J.), Forner, A., Bridgewater, J., Valle, J.W., and Gores, G.J. (Gregory)

Abstract

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. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

Published
2020
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7. Death by association: BH3 domain-only proteins and liver injury

Author

Baskin-Bey, E.S. and Gores, G.J.

Subjects
Apoptosis -- Research, Liver diseases -- Research, Protein research, Biological sciences
Abstract

Apoptosis, a prominent form of cell death, is a prime feature of many acute and chronic liver diseases. Apoptosis requires mitochondrial dysfunction, which is regulated by proteins of the Bc1-2 family. Whether or not a cell should live or die is controlled by the interaction of multidomain Bc1-2 proteins with proapoptotic BH3 domain-only proteins of this family. Current models suggest multidomain, antiapoptotic Bc1-2 proteins prevent mitochondrial dysfunction by sequestering and/or preventing activation of its proapoptotic relatives. BH3-only proteins initiate cell death by neutralizing and or ligating multidomain prosurvival Bc1-2 proteins. Thus BH3 domain-only proteins are paramount in the apoptotic process as exemplified by the role of the BH3 domain-only protein Bid in liver injury. In this concise review, we will focus on how these BH3 domain-only proteins are regulated in the cell, their association with the Bc1-2 family of proteins, and finally, current information regarding their involvement in liver cell apoptosis and injury. apoptosis; mitochondria; death receptors

Published
2005

9. Cathepsin B inactivation attenuates hepatocyte apoptosis and liver damage in steatotic livers after cold ischemia-warm reperfusion injury

Author

Baskin-Bey, E.S., Canbay, A., Bronk, S.F., Werneburg, N., Guicciardi, M.E., Nyberg, S.L., and Gores, G.J.

Subjects
Lysosomes -- Research, Liver diseases -- Research, Biological sciences
Abstract

Hepatic steatosis predisposes the liver to cold ischemia-warm reperfusion (CI/WR) injury by unclear mechanisms. Because hepatic steatosis has recently been associated with a lysosomal pathway of apoptosis, our aim was to determine whether this cell-death pathway contributes to CI/WR injury of steatotic livers. Wild-type and cathepsin B-knockout ([Ctsb.sup.-/-]) mice were fed the methionine/choline-deficient (MCD) diet for 2 wk to induce hepatic steatosis. Mouse livers were stored in the University of Wisconsin solution for 24 h at 4[degrees]C and reperfused for 1 h at 37[degrees]C in vitro. Immunofluorescence analysis of the lysosomal enzymes cathepsin B and D showed a punctated intracellular pattern consistent with lysosomal localization in wild-type mice fed a standard diet after CI/WR injury. In contrast, cathepsin B and D fluorescence became diffuse in livers from wild-type mice fed MCD diet after CI/WR, indicating that lysosomal permeabilization had occurred. Hepatocyte apoptosis was rare in both normal and steatotic livers in the absence of CI/WR injury but increased in wild-type mice fed an MCD diet and subjected to CI/WR injury. In contrast, hepatocyte apoptosis and liver damage were reduced in [Ctsb.sup.-/-] and cathepsin B inhibitor-treated mice fed the MCD diet following CI/WR injury. In conclusion, these findings support a prominent role for the lysosomal pathway of apoptosis in steatotic livers following CI/WR injury. nonalcoholic fatty liver disease; cathepsin D; lysosome; oil red O

Published
2005

15. SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumour Suppressor in Cholangiocarcinoma

Author

Merino-Azpitarte, M., primary, Lozano, E., additional, Perugorria, M.J., additional, Erice, O., additional, Santos-Laso, A., additional, Jiménez-Agüero, R., additional, LaCasta, A., additional, Jalan-Sakrikar, N., additional, Huebert, R.C., additional, Thelen, K.M., additional, Gradilone, S., additional, Aransay, A.M., additional, Lavín, J.L., additional, Fernández-Barrena, M.G., additional, Marzioni, M., additional, Gores, G.J., additional, Bujanda, L., additional, Marín, J.J., additional, and Banales, J.M., additional

Published
2016
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16. Validation of Mesiah Score System in Patients with Hepatocellular Carcinoma

Author

Yang, J.D., primary, Mara, K., additional, Harmsen, W.S., additional, Therneau, T.M., additional, Peck, M., additional, Stauber, R., additional, Degos, F., additional, Blanc, J.-F., additional, Leroy, V., additional, Trinchet, J.C., additional, Duvoux, C., additional, Assenat, E., additional, Klinker, H., additional, Schott, E., additional, Colombo, M., additional, Izzo, F., additional, Marinho, R.T., additional, Pascual, S., additional, Coll, S., additional, Peña, A.M., additional, Stål, P., additional, Haglund, U., additional, Johnson, P., additional, Evans, J., additional, Meyer, T., additional, Suddle, A., additional, Fenwick, S., additional, Castel, H., additional, Schwartz, M., additional, Gores, G.J., additional, and Roberts, L.R., additional

Published
2016
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21. THU-071 - Validation of Mesiah Score System in Patients with Hepatocellular Carcinoma

Author

Yang, J.D., Mara, K., Harmsen, W.S., Therneau, T.M., Peck, M., Stauber, R., Degos, F., Blanc, J.-F., Leroy, V., Trinchet, J.C., Duvoux, C., Assenat, E., Klinker, H., Schott, E., Colombo, M., Izzo, F., Marinho, R.T., Pascual, S., Coll, S., Peña, A.M., Stål, P., Haglund, U., Johnson, P., Evans, J., Meyer, T., Suddle, A., Fenwick, S., Castel, H., Schwartz, M., Gores, G.J., and Roberts, L.R.

Published
2016
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22. Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.

Author

Escande, C., Chini, C.C., Nin, V., Dykhouse, K.M., Novak, C.M., Levine, J., Deursen, J.M.A. van, Gores, G.J., Chen, J., Lou, Z., Chini, E.N., Escande, C., Chini, C.C., Nin, V., Dykhouse, K.M., Novak, C.M., Levine, J., Deursen, J.M.A. van, Gores, G.J., Chen, J., Lou, Z., and Chini, E.N.

Abstract

Contains fulltext : 88193.pdf (publisher's version ) (Open Access), The enzyme sirtuin 1 (SIRT1) is a critical regulator of many cellular functions, including energy metabolism. However, the precise mechanisms that modulate SIRT1 activity remain unknown. As SIRT1 activity in vitro was recently found to be negatively regulated by interaction with the deleted in breast cancer-1 (DBC1) protein, we set out to investigate whether DBC1 regulates SIRT1 activity in vivo. We found that DBC1 and SIRT1 colocalized and interacted, and that DBC1 modulated SIRT1 activity, in multiple cell lines and tissues. In mouse liver, increased SIRT1 activity, concomitant with decreased DBC1-SIRT1 interaction, was detected after 24 hours of starvation, whereas decreased SIRT1 activity and increased interaction with DBC1 was observed with high-fat diet (HFD) feeding. Consistent with the hypothesis that DBC1 is crucial for HFD-induced inhibition of SIRT1 and for the development of experimental liver steatosis, genetic deletion of Dbc1 in mice led to increased SIRT1 activity in several tissues, including liver. Furthermore, DBC1-deficient mice were protected from HFD-induced liver steatosis and inflammation, despite the development of obesity. These observations define what we believe to be a new role for DBC1 as an in vivo regulator of SIRT1 activity and liver steatosis. We therefore propose that the DBC1-SIRT1 interaction may serve as a new target for therapies aimed at nonalcoholic liver steatosis.

Published
2010

29. 395 SURVIVAL OF PATIENTS RECEIVING YTTRIUM-90 MICROSPHERES VS CHEMOEMBOLIZATION FOR UNRESECTABLE HEPATOCELLULAR CARCINOMA

Author

Moreno-Luna, L.E., primary, Paz-Fumagalli, R., additional, Harnois, D.M., additional, de Groen, P.C., additional, Lazaridis, K.N., additional, Menon, K.V.N., additional, La Russo, N.F., additional, Alberts, S.R., additional, Gores, G.J., additional, Therneau, T.M., additional, Wiseman, G.A., additional, Andrews, J.C., additional, and Roberts, L.R., additional

Published
2008
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48. Diagnosis and staging of hepatocellular carcinoma

Author

Talwalkar, J.A. and Gores, G.J.

Abstract

The diagnosis of hepatocellular carcinoma (HCC) includes detection of the index lesion, staging of the lesion within the liver, and assessment for extrahepatic metastasis. HCC is a highly vascular neoplasm usually arising in a cirrhotic liver. Based on this concept, consensus criteria have been developed for the radiographic diagnosis of HCC. These include: (1) identification of a mass >2 cm in diameter in a cirrhotic liver in 2 imaging modalities, and (2) contrast enhancement on computed tomography, magnetic resonance, or angiography. A mass lesion within a cirrhotic liver in the presence of a serum @a-fetoprotein level >400 ng/mL also is diagnostic. For lesions <2 cm in diameter, histological confirmation is required. Serum markers for the diagnosis of early HCC (<2 cm in diameter) have not been established. Staging HCC for metastases is insensitive and is based on conventional criteria (eg, pulmonary nodules, skeletal metastases, and lymphadenopathy). Additional diagnostic techniques based on cytological advances, genomics, and proteomics are needed for the diagnosis and staging of this highly malignant neoplasm.

Published
2004
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49. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures

Author

Baron, T.H., Harewood, G.C., Rumalla, A., Pochron, N.L., Stadheim, L.M., Gores, G.J., Therneau, T.M., De Groen, P.C., Sebo, T.J., Salomao, D.R., and Kipp, B.R.

Abstract

Background & Aims: Digital image analysis (DIA) allows quantification of nuclear DNA content and may help distinguish benign and malignant strictures of the biliary tract. Methods: One hundred ten consecutive patients undergoing endoscopic retrograde cholangiography for suspicious biliary tract strictures were enrolled in a prospective study comparing the accuracy of DIA and routine cytology (RC). Standard brush cytology sampling was performed twice by using 2 cytology brushes per patient. Both brushes were fixed in a single-specimen vial. Each specimen was formed into 1 pellet, and the sample was equally divided for evaluation by DIA and RC. DNA histograms were generated for ploidy analysis. The DIA criterion for malignancy was demonstration of aneuploidy. Results: Two patients had inadequate samples obtained for DIA analysis, 7 benign patients were excluded because of inadequate follow-up of less than 75 days, and 1 patient was lost to follow-up to clarify malignant versus benign disease. Of the remaining 100 patients, 56 strictures were malignant and 44 were benign. The sensitivities of DIA and RC were 39.3% and 17.9%, respectively (P = 0.014). The specificities of DIA and RC were 77.3% and 97.7%, respectively (P = 0.003). The accuracy of DIA (56.0%) was equivalent to RC (53.0%). Conclusions: DIA is a valuable adjunct to RC for detecting malignant strictures of the biliary tract.

Published
2004
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50. Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome

Author

Strand, S., Strand, D., Seufert, R., Mann, A., Lotz, J., Blessing, M., Lahn, M., Wunsch, A., Broering, D.C., Hahn, U., Grischke, E.M., Rogiers, X., Otto, G., Gores, G.J., and Galle, P.R.

Abstract

Background & Aims: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. Methods: Sera from HELLP patients were analyzed and used in cell culture experiments to study CD95-mediated apoptosis. We established a mouse model for placenta-induced liver damage and used a new therapeutical agent, LY498919, to block CD95 apoptosis. Results: We describe apoptosis in the liver of HELLP patients and cytotoxic activity for primary human hepatocytes in HELLP serum. Blocking of CD95 signaling reduced the cytotoxic activity of HELLP serum. In addition, cytotoxic activity increased as HELLP syndrome developed. Furthermore, CD95L was found to be produced in the placenta and extracts of placenta were cytotoxic for human hepatocytes. Injection of mouse placenta extract in mice induces liver damage that could be prevented by blocking CD95L. Conclusions: Taken together, these data suggest that CD95L derived from the placenta acts systemically and is a primary cause of liver damage in HELLP syndrome. Our results also show that blocking of CD95L can reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages.

Published
2004
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