title: A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain.
abstract: Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Deepitha
authors.initials: D
authors.lastname: Selvaraj
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Vijayan
authors.initials: V
authors.lastname: Gangadharan
authors.affiliation: Department of Surgery, Heidelberg University, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kurejova
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stösser
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schweizerhof
authors.affiliation: Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, 48149 Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.affiliation: University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.affiliation: European Molecular Biology Laboratory, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00015 Monterotondo, Italy; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Heppenstall
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Dental and Medical University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM), Heidelberg University, Ludolph-Krehl-Straße 14, 68167 Mannheim, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Pharmacology Institute, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, Otto Meyerhof Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany. Electronic address: rohini.kuner@pharma.uni-heidelberg.de.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D020533:Angiogenesis Inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1