Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

Paula Hoffmeister-Wittmann^{1

2}, Andreas Mock^{1

3

4

5}, Federico Nichetti^{6

7}, Felix Korell^{4

8}, Christoph E Heilig^{3

4}, Anna-Lena Scherr¹, Michael Günther^{4

5}, Thomas Albrecht^{9

10}, Eblina Kelmendi¹, Kaiyu Xu¹, Luisa Nader¹, Annika Kessler¹, Nathalie Schmitt¹, Sarah Fritzsche^{9

10}, Sofia Weiler^{9

10}, Benjamin Sobol¹, Albrecht Stenzinger⁹, Stefan Boeck^{4

11}, Christoph B Westphalen^{4

11}, Klaus Schulze-Osthoff^{4

12}, Jörg Trojan^{4

13}, Thomas Kindler^{4

14}, Wilko Weichert^{4

15}, Karsten Spiekermann^{3

4

16}, Michael Bitzer^{4

17}, Gunnar Folprecht^{4

18}, Anna L Illert^{4

19

20}, Melanie Boerries^{4

20

21}, Frederick Klauschen^{4

22}, Sebastian Ochsenreither^{4

23

24}, Jens Siveke^{4

25

26}, Sebastian Bauer^{4

27}, Hanno Glimm^{28

29

30

31}, Benedikt Brors⁷, Jennifer Hüllein⁷, Daniel Hübschmann^{4

7

32}, Sebastian Uhrig⁷, Peter Horak^{3

4}, Simon Kreutzfeldt^{3

4}, Jesus M Banales^{33

34}, Christoph Springfeld¹, Dirk Jäger¹, Peter Schirmacher^{9

10}, Stephanie Roessler^{9

10}, Steffen Ormanns^{4

5}, Benjamin Goeppert^{9

10

35}, Stefan Fröhling^{3

4}, Bruno C Köhler^{1

4

10}

Affiliations

¹ Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
² Department of Radiooncology, University Hospital Heidelberg, Heidelberg, Germany.
³ Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ German Cancer Consortium (DKTK), Heidelberg and Partner Sites, Heidelberg, Germany.
⁵ Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Munich, Germany.
⁶ Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
⁷ Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
⁹ Institute for Pathology, University Hospital Heidelberg, Heidelberg, Germany.
¹⁰ Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
¹¹ Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹² Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
¹³ Department of Gastroenterology, Gastrointestinal Medical Oncology, University Hospital Frankfurt, Frankfurt am Main, Germany.
¹⁴ University Cancer Center, University Medical Center Mainz, Germany.
¹⁵ Institute of Pathology, Medical Faculty, Technichal University Munich, Munich, Germany.
¹⁶ Department of Hematology and Medical Oncology, University Hospital Munich, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹⁷ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
¹⁸ Department of Hematology and Medical Oncology, Carl Gustav Carus University Hospital, Dresden, Germany.
¹⁹ Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁰ Comprehensive Cancer Center Freiburg (CCCF), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Institute of Pathology, Charité University Medicine Berlin, Berlin, Germany.
²³ Faculty of Medicine, Charité Comprehensive Cancer Center (CCCC), Humboldt University of Berlin, Berlin, Germany.
²⁴ Department of hematology, medical oncology and tumor immunology, Charité University Medicine Berlin, Berlin, Germany.
²⁵ Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
²⁷ Department for Translational Oncology, West German Tumor Center (WTZ), Essen University Hospital, Essen, Germany.
²⁸ Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²⁹ Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: Germany Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
³⁰ German Cancer Consortium (DKTK) Dresden, Germany.
³¹ Translational Functional Cancer Genomics, National Center für Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
³² Heidelberg Institute for Stem cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
³³ Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Ikerbasque, Network Centre for Biomedical Research in Liver and Digestive Diseases (CIBERehd), San Sebastian, Spain.
³⁴ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
³⁵ Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany.

PMID: 35983950
DOI: 10.1111/liv.15392

Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

Paula Hoffmeister-Wittmann et al. Liver Int. 2022 Dec.

. 2022 Dec;42(12):2855-2870.

doi: 10.1111/liv.15392. Epub 2022 Sep 14.

Authors

Affiliations

¹ Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
² Department of Radiooncology, University Hospital Heidelberg, Heidelberg, Germany.
³ Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ German Cancer Consortium (DKTK), Heidelberg and Partner Sites, Heidelberg, Germany.
⁵ Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Munich, Germany.
⁶ Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
⁷ Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
⁹ Institute for Pathology, University Hospital Heidelberg, Heidelberg, Germany.
¹⁰ Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
¹¹ Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹² Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
¹³ Department of Gastroenterology, Gastrointestinal Medical Oncology, University Hospital Frankfurt, Frankfurt am Main, Germany.
¹⁴ University Cancer Center, University Medical Center Mainz, Germany.
¹⁵ Institute of Pathology, Medical Faculty, Technichal University Munich, Munich, Germany.
¹⁶ Department of Hematology and Medical Oncology, University Hospital Munich, Ludwig-Maximilians-University of Munich, Munich, Germany.
¹⁷ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
¹⁸ Department of Hematology and Medical Oncology, Carl Gustav Carus University Hospital, Dresden, Germany.
¹⁹ Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁰ Comprehensive Cancer Center Freiburg (CCCF), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Institute of Pathology, Charité University Medicine Berlin, Berlin, Germany.
²³ Faculty of Medicine, Charité Comprehensive Cancer Center (CCCC), Humboldt University of Berlin, Berlin, Germany.
²⁴ Department of hematology, medical oncology and tumor immunology, Charité University Medicine Berlin, Berlin, Germany.
²⁵ Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
²⁷ Department for Translational Oncology, West German Tumor Center (WTZ), Essen University Hospital, Essen, Germany.
²⁸ Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
²⁹ Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: Germany Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
³⁰ German Cancer Consortium (DKTK) Dresden, Germany.
³¹ Translational Functional Cancer Genomics, National Center für Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
³² Heidelberg Institute for Stem cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
³³ Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Ikerbasque, Network Centre for Biomedical Research in Liver and Digestive Diseases (CIBERehd), San Sebastian, Spain.
³⁴ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
³⁵ Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany.

PMID: 35983950
DOI: 10.1111/liv.15392

Abstract

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x_L , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x_L and Mcl-1. Expression of Bcl-x_L , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x_L and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-x_L (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x_L induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x_L and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x_L in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x_L as a key protein in cell death resistance of CCA and may pave the way for clinical application.

Keywords: Bcl-2; Bcl-xL; Mcl-1; apoptosis; chemotherapy; cholangiocarcinoma.

PubMed Disclaimer

References

REFERENCES

1. Florio AA, Ferlay J, Znaor A, et al. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012. Cancer. 2020;126(11):2666-2678. doi:10.1002/cncr.32803
1. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588. doi:10.1038/s41575-020-0310-z
1. Bertuccio P, Malvezzi M, Carioli G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71:104-114. doi:10.1016/j.jhep.2019.03.013
1. Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657-1669. doi:10.1136/gutjnl-2011-301748
1. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95-111. doi:10.1038/nrclinonc.2017.157

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Ovid Technologies, Inc.
- Wiley
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

Affiliations

Bcl-x_L as prognostic marker and potential therapeutic target in cholangiocarcinoma

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Research Materials