Chemotherapy Enhances Metastasis Formation via VEGFR-1-Expressing Endothelial Cells

Recent studies suggest that chemotherapy, in addition to its cytotoxic effects on tumor cells, can induce a cascade of host events to support tumor growth and spread. Here, we used an experimental pulmonary metastasis model to investigate the role of this host response in metastasis formation. Mice...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2011-11, Vol.71 (22), p.6976-6985
Hauptverfasser: DAENEN, Laura G. M, ROODHART, Jeanine M. L, VAN AMERSFOORT, Miranda, DEHNAD, Mantre, ROESSINGH, Wijnand, ULFMAN, Laurien H, DERKSEN, Patrick W. B, VOEST, Emile E
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container_end_page 6985
container_issue 22
container_start_page 6976
container_title Cancer research (Chicago, Ill.)
container_volume 71
creator DAENEN, Laura G. M
ROODHART, Jeanine M. L
VAN AMERSFOORT, Miranda
DEHNAD, Mantre
ROESSINGH, Wijnand
ULFMAN, Laurien H
DERKSEN, Patrick W. B
VOEST, Emile E
description Recent studies suggest that chemotherapy, in addition to its cytotoxic effects on tumor cells, can induce a cascade of host events to support tumor growth and spread. Here, we used an experimental pulmonary metastasis model to investigate the role of this host response in metastasis formation. Mice were pretreated with chemotherapy and after clearance of the drugs from circulation, tumor cells were administered intravenously to study potential "protumorigenic" host effects of chemotherapy. Pretreatment with the commonly used chemotherapeutic agents cisplatin and paclitaxel significantly enhanced lung metastasis in this model. This corresponded to enhanced adhesion of tumor cells to an endothelial cell monolayer that had been pretreated with chemotherapy in vitro. Interestingly, chemotherapy exposure enhanced the expression of VEGF receptor 1 (VEGFR-1) on endothelial cells both in vitro and in vivo. Administration of antibodies targeting VEGFR-1 reversed the early retention of tumor cells in the lungs, thereby preventing the formation of chemotherapy-induced pulmonary metastases. The data indicate that chemotherapy-induced expression of VEGFR-1 on endothelial cells can create an environment favorable to tumor cell homing. Inhibition of VEGFR-1 function may therefore be used to counteract chemotherapy-induced retention of tumor cells within the metastatic niche, providing a novel level of tumor control in chemotherapy.
doi_str_mv 10.1158/0008-5472.can-11-0627
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subjects Animals
Antineoplastic agents
Biological and medical sciences
Cell Adhesion
Cercopithecus aethiops
COS Cells
Endothelial Cells - physiology
Lung Neoplasms - secondary
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - pathology
Pharmacology. Drug treatments
Platelet Endothelial Cell Adhesion Molecule-1 - analysis
Tumors
Vascular Endothelial Growth Factor Receptor-1 - analysis
Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-1 - physiology
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
title Chemotherapy Enhances Metastasis Formation via VEGFR-1-Expressing Endothelial Cells
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