title: Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells.
abstract: 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.
authors: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Laura G M
authors: LG
authors: Daenen
authors: Jeanine M L
authors: JM
authors: Roodhart
authors: Miranda
authors: M
authors: van Amersfoort
authors: Mantre
authors: M
authors: Dehnad
authors: Wijnand
authors: W
authors: Roessingh
authors: Laurien H
authors: LH
authors: Ulfman
authors: Patrick W B
authors: PW
authors: Derksen
authors: Emile E
authors: EE
authors: Voest
mesh_terms: D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2