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

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 -