Research Papers:

Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

Andreas Pircher _, Karin Jöhrer, Florian Kocher, Normann Steiner, Ivo Graziadei, Isabel Heidegger, Renate Pichler, Nicolai Leonhartsberger, Christian Kremser, Johann Kern, Gerold Untergasser, Eberhard Gunsilius and Wolfgang Hilbe

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Oncotarget. 2016; 7:20109-20123. https://doi.org/10.18632/oncotarget.7915

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Andreas Pircher1, Karin Jöhrer2, Florian Kocher1,2, Normann Steiner1, Ivo Graziadei3, Isabel Heidegger4, Renate Pichler4, Nicolai Leonhartsberger4, Christian Kremser5, Johann Kern1, Gerold Untergasser1, Eberhard Gunsilius1, Wolfgang Hilbe1,6

1Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria

2Tyrolean Cancer Research Institute, Innsbruck, Austria

3Department of Internal Medicine II, Gastroenterology and Hepatology, Medical University Innsbruck, Innsbruck, Austria

4Department of Urology, Medical University Innsbruck, Innsbruck, Austria

5Department of Radiology, Medical University Innsbruck, Innsbruck, Austria

6Department of Oncology, Hematology and Palliative Care Wilhelminenspital, Vienna, Austria

Correspondence to:

Andreas Pircher, e-mail: [email protected]

Wolfgang Hilbe, e-mail: [email protected]

Keywords: angiogenesis, antiangiogenic therapies, placental growth factor (PlGF), vascular endothelial growth factor (VEGF), Robo4

Received: October 02, 2015     Accepted: February 16, 2016     Published: March 04, 2016


Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development.

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