Abstract LB-186: Differential effects of stress on tumor initiation and progression - role of neuropeptide Y
Authors: Tilan Jason U. , Izycka-Swieszewska Ewa , Earnest Joshua Patrick , Galli Susana , Shabbir Asim , Lu Congyi , Czarnecka Magdalena , Rodriguez Olga , Albanese Christopher , Kitlinska Joanna 
Published: August 2012

Epidemiological and experimental studies suggest that psychosocial stress contributes to cancer development and progression. Yet, the mechanism of this phenomenon is not clear. The goal of our study was to test whether the sympathetic neurotransmitter neuropeptide Y (NPY), which is up-regulated in chronic stress and acts as an angiogenic and growth factor, mediates this process. To this end, wild type (WT) and NPY knockout (NPY KO) mice were treated with a chemical carcinogen, 7,12 dimethylbenz[a]anthracene (DMBA), in the presence of medroxyprogesterone acetate (MPA). To isolate NPY-dependent effects of stress, DMBA/MPA-treated WT and NPY KO mice were subjected to chronic stress (daily cold exposure) for two weeks in the following groups: 1) Control; 2) Early stress during DMBA administration to establish its effect on tumor initiation; 3) Late stress applied when tumors were detectable to determine its effect on their progression. Tumorigenic processes were assessed by monitoring mammary tumor growth, periodical MRI imaging and histopathology of tumor tissues. DMBA/MPA treatment resulted in various neoplastic changes: lymphoma/leukemia (Leu), uterine hemangiomas and angiosarcomas, folliculomas and mammary tumors. The following differences were observed: 1) Under basal conditions, lack of NPY resulted in reduced incidence of Leu and a protective effect on mammary tumor formation (reduced frequency and increased latency) in NPY KO mice suggesting its role in development of these malignancies; 2) early stress increased incidence of uterine angiosarcomas in an NPY-dependent manner. In contrast, a stress-induced increase in frequency of Leu and ovarian folliculoma was observed only in NPY KO mice suggesting that this effect may be mediated by catecholamines (CA), which are excessively released in the absence of an inhibitor of their secretion such as NPY. Surprisingly, early stress had a protective effect on mammary tumor formation that was observed in both WT and NPY KO mice suggesting an NPY-independent mechanism; 3) Late stress accelerated the progression of Leu in an NPY-independent manner. A similar phenomenon was observed in uterine angiosarcomas induced in WT mice, while late stress in NPY KO mice caused their complete regression. These results may be explained by a growth inhibitory effect of CA excessively released in stressed animals devoid of NPY. Lastly, in mammary tumors, stress increased tumor vascularization and proliferation in an NPY-dependent manner. In summary, our data demonstrate potent and differential effects of NPY and other stress mediators on tumor development and progression. These results lay a foundation for further, more comprehensive and mechanistic studies on the effects of stress on particular tumor types. This, in turn, may open new therapeutic and perhaps also preventative avenues for cancer patients, as well as identify populations at risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-186. doi:1538-7445.AM2012-LB-186