Biologic effects of dopamine on tumor vasculature in ovarian carcinoma.
Title | Biologic effects of dopamine on tumor vasculature in ovarian carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Moreno-Smith M, Lee SJoo, Lu C, Nagaraja AS, He G, Rupaimoole R, Han HDong, Jennings NB, Roh J-W, Nishimura M, Kang Y, Allen JK, Armaiz GN, Matsuo K, Shahzad MMK, Bottsford-Miller J, Langley RR, Cole SW, Lutgendorf SK, Siddik ZH, Sood AK |
Journal | Neoplasia |
Volume | 15 |
Issue | 5 |
Pagination | 502-10 |
Date Published | 2013 May |
ISSN | 1476-5586 |
Keywords | Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Benzazepines, Catecholamines, Cell Line, Tumor, Cisplatin, Dopamine, Dopamine Agents, Drug Synergism, Endothelial Cells, Female, Humans, Mice, Mice, Nude, Neovascularization, Pathologic, Ovarian Neoplasms, Pericytes, Receptors, Adrenergic, beta, Receptors, Dopamine, Second Messenger Systems, Stress, Physiological, Xenograft Model Antitumor Assays |
Abstract | 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 mono-phosphate (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. |
Alternate Journal | Neoplasia |
PubMed ID | 23633922 |
PubMed Central ID | PMC3638353 |
Grant List | CA109298 / CA / NCI NIH HHS / United States CA128797 / CA / NCI NIH HHS / United States CA160687 / CA / NCI NIH HHS / United States F31CA126474 / CA / NCI NIH HHS / United States P30 CA016672 / CA / NCI NIH HHS / United States P50 CA098258 / CA / NCI NIH HHS / United States P50CA083639 / CA / NCI NIH HHS / United States P50CA098258 / CA / NCI NIH HHS / United States R01 CA160687 / CA / NCI NIH HHS / United States RC2GM092599 / GM / NIGMS NIH HHS / United States T32 CA101642 / CA / NCI NIH HHS / United States U54 CA151668 / CA / NCI NIH HHS / United States U54CA151668 / CA / NCI NIH HHS / United States U54CA96297 / CA / NCI NIH HHS / United States U54CA96300 / CA / NCI NIH HHS / United States |