title: Bcl-xL is an oncogenic driver in colorectal cancer.
abstract: Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xL(IEC-KO)). If challenged in an inflammation-driven tumor model, Bcl-xL(IEC-KO) mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application.
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Scherr
authors.affiliation: Clinical Cooperation Unit (CCU) Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|Institute of Pathology, Department of Surgical Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.affiliation: Division of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Mariam
authors.initials: M
authors.lastname: Salou
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Praveen
authors.initials: P
authors.lastname: Radhakrishnan
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Duglova
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Heller
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Keim
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kautz
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Jassowicz
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Elssner
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Pathology, University Medical Center Mainz, Mainz 55131, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: Department of Internal Medicine II, Marien-Hospital, Wesel 46483, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze-Bergkamen
authors.affiliation: National Center for Tumor Diseases, Department of Medical Oncology and Heidelberg University Hospital, Internal Medicine VI, 69120 Heidelberg, Germany.
authors.forename: Bruno Christian
authors.initials: BC
authors.lastname: Koehler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009596:Nitrophenols / Q000494:pharmacology; D009857:Oncogenes; D009928:Organ Specificity; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein