Oncotarget

Research Papers:

Inhibition of the transcriptional repressor complex Bcl-6/BCoR induces endothelial sprouting but does not promote tumor growth

Elisabeth Buchberger, Dietmar Payrhuber, Miriam El Harchi, Branislav Zagrapan, Katharina Scheuba, Anna Zommer, Edina Bugyik, Balazs Dome, Julia Barbara Kral, Waltraud Cornelia Schrottmaier, Gernot Schabbauer, Peter Petzelbauer, Marion Gröger, Martin Bilban and Christine Brostjan _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:552-564. https://doi.org/10.18632/oncotarget.13477

Metrics: PDF 2223 views  |   HTML 3542 views  |   ?  


Abstract

Elisabeth Buchberger1,2, Dietmar Payrhuber1, Miriam El Harchi1, Branislav Zagrapan1, Katharina Scheuba1, Anna Zommer1, Edina Bugyik3,4,5, Balazs Dome6,7,8, Julia Barbara Kral9, Waltraud Cornelia Schrottmaier9, Gernot Schabbauer9, Peter Petzelbauer10, Marion Gröger11, Martin Bilban12,13, Christine Brostjan1,2

1Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria

2Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

3First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

4Department of Thoracic Surgery, Semmelweis University - National Institute of Oncology, Budapest, Hungary

5Hungarian Academy of Sciences Postdoctoral Research Programme, Budapest, Hungary

6Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria

7Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria

8National Koranyi Institute of Pulmonology, Budapest, Hungary

9Institute of Physiology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

10Department of Dermatology, Medical University of Vienna, General Hospital, Vienna, Austria

11Core Facility Imaging, Medical University of Vienna, Vienna, Austria

12Department of Laboratory Medicine, Medical University of Vienna, General Hospital, Vienna, Austria

13Core Facility Genomics, Medical University of Vienna, Vienna, Austria

Correspondence to:

Christine Brostjan, email: [email protected]

Keywords: 79-6, Bcl-6, BCoR, colorectal carcinoma, vascular sprouting

Received: June 20, 2016     Accepted: November 14, 2016     Published: November 21, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 13477