Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B
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Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B. / Wroblewski, M; Bauer, R; Cubas Córdova, M; Udonta, F; Ben-Batalla, I; Legler, K; Hauser, C; Egberts, J; Janning, M; Velthaus, J; Schulze, Christian; Pantel, K; Bokemeyer, C; Loges, S.
in: NAT COMMUN, Jahrgang 8, Nr. 1, 16.08.2017, S. 269.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B
AU - Wroblewski, M
AU - Bauer, R
AU - Cubas Córdova, M
AU - Udonta, F
AU - Ben-Batalla, I
AU - Legler, K
AU - Hauser, C
AU - Egberts, J
AU - Janning, M
AU - Velthaus, J
AU - Schulze, Christian
AU - Pantel, K
AU - Bokemeyer, C
AU - Loges, S
PY - 2017/8/16
Y1 - 2017/8/16
N2 - 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.Resistance towards VEGF-centered anti-angiogenic therapy is an important clinical challenge. Here, the authors show that mast cells mediate resistance to anti-angiogenetic inhibitors by altering the proliferative and organizational state of endothelial cells through mobilization of FGF-1 and GM-CSF from the tumor matrix and secretion of FGF-2.
AB - 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.Resistance towards VEGF-centered anti-angiogenic therapy is an important clinical challenge. Here, the authors show that mast cells mediate resistance to anti-angiogenetic inhibitors by altering the proliferative and organizational state of endothelial cells through mobilization of FGF-1 and GM-CSF from the tumor matrix and secretion of FGF-2.
KW - Angiogenesis Inhibitors
KW - Animals
KW - Anti-Asthmatic Agents
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Cromolyn Sodium
KW - Endothelial Cells
KW - Extracellular Matrix
KW - Fibroblast Growth Factor 1
KW - Fibroblast Growth Factor 2
KW - Granulocyte-Macrophage Colony-Stimulating Factor
KW - Granzymes
KW - Human Umbilical Vein Endothelial Cells
KW - Laminin
KW - Mast Cells
KW - Mice
KW - Neoplasms
KW - Neovascularization, Pathologic
KW - Vascular Endothelial Growth Factor A
KW - Vascular Endothelial Growth Factor Receptor-2
KW - Vitronectin
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41467-017-00327-8
DO - 10.1038/s41467-017-00327-8
M3 - SCORING: Journal article
C2 - 28814715
VL - 8
SP - 269
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -