Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors.
Neuropeptide Y (NPY) is a sympathetic neurotransmitter recently found to be potently angiogenic and growth promoting for endothelial, vascular smooth muscle and neuronal cells. NPY and its cognate receptors, Y1, Y2 and Y5, are expressed in neural crest-derived tumors; however, their role in regulation of growth is unknown. The effect of NPY on the growth and vascularization of neuroendocrine tumors was tested using three types of cells: neuroblastoma, pheochromocytoma, and Ewing's sarcoma family of tumors (ESFT). The tumors varied in expression of NPY receptors, which was linked to differential functions of the peptide. NPY stimulated proliferation of neuroblastoma cells via Y2/Y5Rs and inhibited ESFT cell growth by Y1/Y5-mediated apoptosis. In both tumor types, NPY receptor antagonists altered basal growth levels, indicating a regulatory role of autocrine NPY. In addition, the peptide released from the tumor cells stimulated endothelial cell proliferation, which suggests its paracrine angiogenic effects. In nude mice xenografts, exogenous NPY stimulated growth of neuroblastoma tumors, whereas it increased apoptosis and reduced growth of ESFT. However, in both tumors, NPY treatment led to an increase in tumor vascularization. Taken together, this is the first report of NPY being a growth-regulatory factor for neuroendocrine tumors, acting both by autocrine activation of tumor cell proliferation or apoptosis and by angiogenesis. NPY and its receptors may become targets for novel approaches in the treatment of these diseases, directed against both tumor cell proliferation and angiogenesis.
Kitlinska
Joanna
J
Department of Physiology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia 20057, USA. jbk4@georgetown.edu
Abe
Ken
K
Kuo
Lydia
L
Pons
Jennifer
J
Yu
Muchieh
M
Li
Lijun
L
Tilan
Jason
J
Everhart
Lindsay
L
Lee
Edward W
EW
Zukowska
Zofia
Z
Toretsky
Jeffrey A
JA
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009478:Neuropeptide Y / Q000378:metabolism*; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000145:classification / Q000502:physiology*; D014183:Transplantation, Heterologous
D017077:Culture Media, Conditioned; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D020928:Mitogen-Activated Protein Kinases