Research Papers:

Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer

Linda Zuurbier, Arman Rahman, Martijn Cordes, Jennifer Scheick, Tse J. Wong, François Rustenburg, Jesu Christopher Joseph, Peter Dynoodt, Rory Casey, Paul Drillenburg, Michael Gerhards, Ana Barat, Rut Klinger, Bozena Fender, Darran P. O’Connor, Johannes Betge, Matthias P. Ebert, Timo Gaiser, Jochen H.M. Prehn, Arjan W. Griffioen, Nicole C. T. van Grieken, Bauke Ylstra, Annette T. Byrne, Laurens G. van der Flier, William M. Gallagher and Ruben Postel _

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Oncotarget. 2017; 8:42949-42961. https://doi.org/10.18632/oncotarget.17306

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Linda Zuurbier1,*, Arman Rahman2,*, Martijn Cordes3, Jennifer Scheick4, Tse J. Wong4, François Rustenburg3, Jesu Christopher Joseph2, Peter Dynoodt2, Rory Casey2, Paul Drillenburg5, Michael Gerhards5, Ana Barat6, Rut Klinger7, Bozena Fender2, Darran P. O’Connor8, Johannes Betge9, Matthias P. Ebert9, Timo Gaiser10, Jochen H.M. Prehn6, Arjan W. Griffioen4, Nicole C. T. van Grieken3, Bauke Ylstra3, Annette T. Byrne6, Laurens G. van der Flier1, William M. Gallagher2,7,* and Ruben Postel1,*

1SomantiX BV, Utrecht, The Netherlands

2OncoMark Ltd, Dublin, Ireland

3Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

4Department of Medical Oncology, Angiogenesis Laboratory, VU University Medical Center, Amsterdam, The Netherlands

5Department of Pathology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

6Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

7UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland

8Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

9Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

10Institute of Pathology, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

*These authors have contributed equally to this work

Correspondence to:

Ruben Postel, email: [email protected]

William M. Gallagher, email: [email protected]

Keywords: apelin, biomarker, bevacizumab response, VEGF, colorectal cancer

Received: November 08, 2016    Accepted: April 04, 2017    Published: April 21, 2017


Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced genes were overexpressed in tumour ECs; these genes could relate to bvz response and serve as potential predictive biomarkers. Transcriptional profiling revealed a total of 2,610 differentially expressed genes when tumour and normal ECs were compared. To explore their relation to bvz response, the mRNA expression levels of top-ranked genes were examined using quantitative PCR in 30 independent tumour tissues from CRC patients that received bvz in the adjuvant setting. These analyses revealed that the expression of MMP12 and APLN mRNA was significantly higher in bvz non-responders compared to responders. At the protein level, high APLN expression was correlated with poor progression-free survival in bvz-treated patients. Thus, high APLN expression may represent a novel predictive biomarker for bvz unresponsiveness.

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