The pain associated with many cancers decreases the patient’s quality of life. Tumors are often surrounded by nerves and blood vessels, and vascular remodeling factors, such as vascular endothelial growth factor (VEGF), are often secreted by tumors. Selvaraj et al. found that VEGF signaling enhances peripheral neuron sensitivity in mouse cancer models. Immunostaining analyses revealed an abundance of VEGF receptor 1 (VEGFR1) over the cell body of sensory neurons in mouse dorsal root ganglia (DRG) sections, cultured mouse DRG neurons, and peripheral nerves in mouse hind paw skin. Intraplantar injections of VEGF-A, but not other VEGF family ligands, dose-dependently increased mechanical and thermal sensitivity in the hind paw of mice. This increased sensitivity was blocked by pretreating the hind paw with a neutralizing antibody to VEGFR1 but not by antibodies against VEGFR2 or neuropilins, and it was absent in mice genetically engineered with a VEGFR1 lacking the kinase domain. An ex vivo preparation of paw skin with the attached saphenous nerve also showed increased mechanical sensitivity in the presence of VEGF-A. Exposing DRG neuron cultures to various kinase inhibitors revealed several downstream mediators of the VEGF-A/VEGFR1 pathway that mediated increased sensitivity to mechanical or thermal stimulation or both. VEGFR1 abundance in DRG neurons and nociceptive sensitivity were increased in mice bearing osteolytic saracoma allografts. Sensory neuron-specific knockdown or conditional deletion of VEGFR1 in mice with either osteolytic saracoma or lung cancer allografts prevented tumor-induced mechanical and thermal sensitivity, as well as neuronal hypertrophy and sprouting around the growing tumor. Local injection of blocking antibodies to VEGF-A or VEGFR1 or injection of the extracellular ligand-binding domain of VEGFR1 attenuated osteolytic saracoma-induced hypersensitivity to pain in mice. In a mouse model of breast cancer metastasis to large skeletal bones, systemic administration of the VEGFR1-blocking antibody reduced both induced mechanical sensitivity and spontaneous (unprovoked) displays of limb pain, as well as reduced neuronal sprouting around the tumor. In human patients with pancreatic ductal adenocarcinoma, patient-reported perceptions of pain positively correlated with intensity and area of VEGFR1 staining in tumor-associated neurons in pancreatic biopsies. The findings suggest that VEGFR-blocking antibodies might suppress pain in cancer patients.
D. Selvaraj, V. Gangadharan, C. W. Michalski, M. Kurejova, S. Stӧsser, K. Srivastava, M. Schweizerhof, J. Waltenberger, N. Ferrara, P. Heppenstall, M. Shibuya, H. G. Augustin, R. Kuner, A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27, 780–796 (2015). [PubMed]