Abstract
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.
Highlights
Angiogenesis, the formation of blood vessels, is a hallmark of cancer that significantly contributes to cancer progression and metastasis [1]
When vascular endothelial growth factor (VEGF) is neutralized by antibodies (e.g. Bevacizumab) or VEGF-receptor (VEGFR) signaling is inhibited by receptor-tyrosine kinase inhibitors (e.g. Sunitinib, Sorafenib), compensatory angiogenic pathways and cytokines can be upregulated thereby stimulating resident endothelial cells [5]
Intensive proangiogenic cytokine measurements for biomarker development during antiangiogenic therapies, either with monoclonal antibodies or tyrosine kinase inhibitors (TKI) targeting VEGF/R signaling, have been performed previously [12, 23−28]. Most of these studies reported an upregulation of proangiogenic factors like VEGF, platelet derived growth factor (PDGF), placental growth factor (PlGF) and hepatocyte growth factor (HGF) during therapy [23, 24, 29], which may reflect an increase of tumor hypoxia during antiangiogenic therapy
Summary
Angiogenesis, the formation of blood vessels, is a hallmark of cancer that significantly contributes to cancer progression and metastasis [1]. Increased tumor angiogenesis limits prognosis and overall survival of cancer patients [1]. The success of blocking angiogenesis by inhibiting vascular endothelial growth factor (VEGF) is limited by insufficient efficacy and the development of resistance [2,3,4,5]. An important driver for development of therapy resistance is the increase of tumor hypoxia during antiangiogenic treatment [7] leading to the upregulation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1A). HIF-1A activates survival pathways in tumor cells and increases production of angiogenic growth factors such as VEGF or fibroblast growth factor (FGF) and others, thereby inducing more aggressive tumor growth, influencing endothelial cell behavior, and promoting therapy resistance [7, 8]. When VEGF is neutralized by antibodies (e.g. Bevacizumab) or VEGF-receptor (VEGFR) signaling is inhibited by receptor-tyrosine kinase inhibitors (e.g. Sunitinib, Sorafenib), compensatory angiogenic pathways and cytokines can be upregulated thereby stimulating resident endothelial cells [5]
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