Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B

M. Wroblewski, R. Bauer, M. Cubas Córdova, F. Udonta, I. Ben-Batalla, K. Legler, C. Hauser, J. Egberts, M. Janning, J. Velthaus, C. Schulze, K. Pantel, C. Bokemeyer and S. Loges ()
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M. Wroblewski: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
R. Bauer: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
M. Cubas Córdova: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
F. Udonta: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
I. Ben-Batalla: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
K. Legler: University Medical Center Schleswig-Holstein (UKSH)
C. Hauser: University Medical Center Schleswig-Holstein (UKSH)
J. Egberts: University Medical Center Schleswig-Holstein (UKSH)
M. Janning: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
J. Velthaus: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
C. Schulze: University Medical Center Hamburg-Eppendorf
K. Pantel: Center of Experimental Medicine University Medical Center Hamburg-Eppendorf
C. Bokemeyer: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
S. Loges: University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Resistance towards VEGF-centered anti-angiogenic therapy still represents a substantial clinical challenge. We report here that mast cells alter the proliferative and organizational state of endothelial cells which reduces the efficacy of anti-angiogenic therapy. Consequently, absence of mast cells sensitizes tumor vessels for anti-angiogenic therapy in different tumor models. Mechanistically, anti-angiogenic therapy only initially reduces tumor vessel proliferation, however, this treatment effect was abrogated over time as a result of mast cell-mediated restimulation of angiogenesis. We show that mast cells secrete increased amounts of granzyme b upon therapy, which mobilizes pro-angiogenic laminin- and vitronectin-bound FGF-1 and GM-CSF from the tumor matrix. In addition, mast cells also diminish efficacy of anti-angiogenic therapy by secretion of FGF-2. These pro-angiogenic factors act beside the targeted VEGFA–VEGFR2-axis and reinduce endothelial cell proliferation and angiogenesis despite the presence of anti-angiogenic therapy. Importantly, inhibition of mast cell degranulation with cromolyn is able to improve efficacy of anti-angiogenic therapy. Thus, concomitant mast cell-targeting might lead to improved efficacy of anti-angiogenic therapy.

Date: 2017
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DOI: 10.1038/s41467-017-00327-8

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