Influence of morphine on pericyte-endothelial interaction: implications for antiangiogenic therapy.
Morphine stimulates tumor angiogenesis and cancer progression in mice. We examined if morphine influences endothelial-pericyte interaction via platelet-derived growth factor-BB (PDGF-BB) and PDGF receptor-β (PDGFR-β). Clinically relevant doses of morphine stimulated PDGF-BB secretion from human umbilical vein endothelial cells and activated PDGFR-β and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation in human pericytes. These in vitro effects of morphine were translated into promotion of tumor angiogenesis in a transgenic mice model of breast cancer when treated with clinically used dose of morphine. Increased vessel-associated immunoreactivity of desmin and PDGFR-β was observed on pericytes in tumors of morphine-treated mice. These data suggest that morphine potentiates endothelial-pericyte interaction via PDGF-BB/PDGFR-β signaling and promotes tumor angiogenesis, pericyte recruitment, and coverage of tumor vessels. We speculate that morphine may impair the effectiveness of antiangiogenic therapy by influencing vascular pericyte coverage.
Vascular Biology Center and Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical School, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Kathryn
K
Luk
Sonja
S
Boatman
Katherine N
KN
Johnson
Olivia A
OA
Dudek
Natalie
N
Ristau
Derek
D
Vang
Julia
J
Nguyen
Kalpna
K
Gupta