TY - JOUR
T1 - Rapid stromal remodeling by short-term VEGFR2 inhibition increases chemotherapy delivery in esophagogastric adenocarcinoma
AU - Steins, Anne
AU - Klaassen, Remy
AU - Jacobs, Igor
AU - Schabel, Matthias C.
AU - van Lier, Monique G.J.T.B.
AU - Ebbing, Eva A.
AU - Hectors, Stefanie J.
AU - Tas, Sander W.
AU - Maracle, Chrissta X.
AU - Punt, Cornelis J.A.
AU - Siebes, Maria
AU - Bergman, Jacques J.G.H.M.
AU - Medema, Jan Paul
AU - Wilmink, Johanna W.
AU - Mathot, Ron A.A.
AU - Strijkers, Gustav J.
AU - Bijlsma, Maarten F.
AU - van Laarhoven, Hanneke W.M.
N1 - Publisher Copyright:
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Anti-angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient-derived xenograft (PDX) models of EAC were subjected to long-term and short-term treatment with anti-VEGFR2 therapy followed by chemotherapy injection or multi-agent dynamic contrast-enhanced (DCE-) MRI and vascular casting. Long-term anti-VEGFR2-treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short-term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short-term anti-angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long-term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti-angiogenic therapy combined with chemotherapy in EAC patients.
AB - Anti-angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient-derived xenograft (PDX) models of EAC were subjected to long-term and short-term treatment with anti-VEGFR2 therapy followed by chemotherapy injection or multi-agent dynamic contrast-enhanced (DCE-) MRI and vascular casting. Long-term anti-VEGFR2-treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short-term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short-term anti-angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long-term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti-angiogenic therapy combined with chemotherapy in EAC patients.
KW - DCE-MRI
KW - anti-angiogenic therapy
KW - chemotherapy
KW - esophagogastric adenocarcinoma
KW - stromal remodeling
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U2 - 10.1002/1878-0261.12599
DO - 10.1002/1878-0261.12599
M3 - Article
C2 - 31733011
AN - SCOPUS:85081027053
SN - 1574-7891
VL - 14
SP - 704
EP - 720
JO - Molecular Oncology
JF - Molecular Oncology
IS - 4
ER -