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[Cancer Research 62, 4491-4498, August 1, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Morphine Stimulates Angiogenesis by Activating Proangiogenic and Survival-promoting Signaling and Promotes Breast Tumor Growth1

Kalpna Gupta2, Smita Kshirsagar, Liming Chang, Robert Schwartz, Ping-Y. Law, Doug Yee and Robert P. Hebbel

Departments of Medicine [K. G., L. C., R. S., D. Y., R. P. H.] and Pharmacology [S. K., P-Y. L.], University of Minnesota Medical School, Minneapolis, Minnesota 55455

Morphine is used to treat pain in several medical conditions including cancer. Here we showthat morphine, in a concentration typical of that observed in patients’ blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. It does so by activating mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation via Gi/Go-coupled G protein receptors and nitric oxide in these microvascular endothelial cells. Other contributing effects of morphine include activation of the survival signal PKB/Akt, inhibition of apoptosis, and promotion of cell cycle progression by increasing cyclin D1. Consistent with these effects, morphine in clinically relevant doses promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression. These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers.




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Copyright © 2002 by the American Association for Cancer Research.