Journal
NEOPLASIA
Volume 15, Issue 5, Pages 502-+Publisher
NEOPLASIA PRESS
DOI: 10.1593/neo.121412
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Funding
- National Cancer Institute [F31CA126474]
- National Institute of Health (NIH) [CA101642, CA109298, P50CA083639, P50CA098258, CA128797, RC2GM092599, U54CA151668, U54CA96300, U54CA96297, CA160687]
- GCF-Molly Cade ovarian cancer research grant
- NIH/Eunice Kennedy Shriver National Institute of Child Health Baylor Woman's Reproductive Health Research scholarship grant
- Ovarian Cancer Research Fund Program Project Development grant
- Department of Defense [OC073399, W81XWH-10-1-0158, OC100237, BC085265]
- Cancer Prevention Research Institute of Texas (CPRIT) grant [RP110595]
- Zarrow Foundation7
- Betty Ann Asche Murray Distinguished Professorship
- Marcus Foundation
- RGK Foundation
- Gilder Foundation
- estate of C.G. Johnson Jr
- Laura and John Arnold Foundation
- Blanton-Davis Ovarian Cancer Research Program
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Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine monophosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.
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