title: Inhibition of the transcriptional repressor complex Bcl-6/BCoR induces endothelial sprouting but does not promote tumor growth.
abstract: The oncogenic potential of the transcriptional repressor Bcl-6 (B-cell lymphoma 6) was originally discovered in non-Hodgkin patients and the soluble Bcl-6 inhibitor 79-6 was developed to treat diffuse large B-cell lymphomas with aberrant Bcl-6 expression. Since we found Bcl-6 and its co-repressor BCoR (Bcl-6 interacting co-repressor) to be regulated in human microvascular endothelium by colorectal cancer cells, we investigated their function in sprouting angiogenesis which is central to tumor growth. Based on Bcl-6/BCoR gene silencing we found that the transcriptional repressor complex in fact constitutes an endogenous inhibitor of vascular sprouting by supporting the stalk cell phenotype: control of Notch target genes (HES1, HEY1, DLL4) and cell cycle regulators (cyclin A and B1). Thus, when endothelial cells were transiently transfected with Bcl-6 and/or BCoR siRNA, vascular sprouting was prominently induced. Comparably, when the soluble Bcl-6 inhibitor 79-6 was applied in the mouse retina model of physiological angiogenesis, endothelial sprouting and branching were significantly enhanced. To address the question whether clinical treatment with 79-6 might therefore have detrimental therapeutic effects by promoting tumor angiogenesis, mouse xenograft models of colorectal cancer and diffuse large B-cell lymphoma were tested. Despite a tendency to increased tumor vessel density, 79-6 therapy did not enhance tumor expansion. In contrast, growth of colorectal carcinomas was significantly reduced which is likely due to a combined 79-6 effect on cancer cells and tumor stroma. These findings may provide valuable information regarding the future clinical development of Bcl-6 inhibitors.
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchberger
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Payrhuber
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Miriam
authors.initials: M
authors.lastname: El Harchi
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Zagrapan
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Scheuba
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Zommer
authors.affiliation: First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.|Department of Thoracic Surgery, Semmelweis University - National Institute of Oncology, Budapest, Hungary.|Hungarian Academy of Sciences Postdoctoral Research Programme, Budapest, Hungary.
authors.forename: Edina
authors.initials: E
authors.lastname: Bugyik
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.|Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.|National Koranyi Institute of Pulmonology, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
authors.affiliation: Institute of Physiology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia Barbara
authors.initials: JB
authors.lastname: Kral
authors.affiliation: Institute of Physiology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Waltraud Cornelia
authors.initials: WC
authors.lastname: Schrottmaier
authors.affiliation: Institute of Physiology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.affiliation: Department of Dermatology, Medical University of Vienna, General Hospital, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.affiliation: Core Facility Imaging, Medical University of Vienna, Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Gröger
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, General Hospital, Vienna, Austria.|Core Facility Genomics, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.|Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Brostjan
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C486398:BCL6B protein, human; C411984:BCOR protein, human; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D051880:Receptors, Notch; D012097:Repressor Proteins
keywords: 79-6; BCoR; Bcl-6; colorectal carcinoma; vascular sprouting