Abstract 406: Mechanisms of stress-buffering effects of dopamine on tumor vasculature
Authors: Lee Sun Joo , Moreno-Smith Myrthala , Han Hee Dong , Lu Chunhua , Roh Ju-Won , Nishimura Masato , Allen Julie K. , Jennings Nicholas B. , Matsuo Koji , Shahzad Mian M.K. , Lutgendorf Susan K. , Sood Anil K. 
Published: August 2014

Abstract
Chronic stress is known to promote tumor growth by activating the sympathetic nervous system (SNS) with resultant increases in norepinephrine (NE) and epinephrine (E). In contrast to NE and E, dopamine (DA) levels are low under chronic stress conditions. We have recently demonstrated that dopamine replacement in mice exposed to daily restraint stress can reverse the stimulatory effects of NE and E on ovarian cancer growth. Ovarian tumor tissues from stressed mice treated with dopamine showed significant increases in pericyte coverage of tumor microvessels. The focus of the current study was to examine the mechanisms by which dopamine treatment affected pericyte coverage of tumor endothelial cells under stress conditions. Female nude mice were subjected to chronic stress using the restraint-stress procedure. Tumor formation was induced by injecting the SKOV3 ip1 or HeyA8 ovarian cancer cells into the peritoneal cavity. Stressed and non-stressed mice were divided into four treatment groups: Control (PBS), DA, DA plus butaclamol (DR1 antagonist) and DA plus eticlopride (DR2 antagonist). Following therapy, harvested tumors were examined for microvessel density (MVD), vascular maturation (pericyte coverage) and proliferating cell nuclear antigen (PCNA). Expression of DA receptors (DR1-DR5) was analyzed by RT-PCR and Western blotting. Mice exposed to daily restraint stress showed 2-fold increased SKOV3ip1-tumor growth compared to non-stressed mice; treatment with DA alone resulted in 78% (p&lt;0.01) decrease in tumor growth and 68% (p&lt;0.01) decrease in MVD compared to control stressed mice. Similarly, DA/butaclamol combined treatment led to 71% (p&lt;0.01) reduction in tumor growth and a 65% (p&lt;0.01) decrease in MVD. Eticlopride in combination with DA reversed the inhibitory effects of DA on tumor growth. Furthermore, in stressed mice, daily dopamine treatment resulted in significant increase in pericyte coverage (51.4%; p&lt;0.001) compared to controls. This effect was abrogated by butaclamol (44%; p&lt;0.01), but not by eticlopride treatment. Similar results were obtained in stressed mice bearing HeyA8-tumors. In T10.5-pericyte like cells, treatment with DA, DA plus NE, DA agonist: SKF38393 or PDGFBB increased significantly cell migration. No significant changes were noted with NE alone or DA plus butaclamol treatments. In MOEC, no significant changes in cell migration were observed under these experimental conditions. Collectively, our data indicate that DA, acting through DR1, could stimulate recruitment of pericytes to tumor endothelial cells, and promote vascular maturation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 406. doi:10.1158/1538-7445.AM2011-406