Cancer is influenced by an individual's interaction with its physical and social environment, yet the underlying mechanisms are poorly defined. Epidemiological studies have revealed that social support is linked to improved health outcomes among cancer patients whereas social isolation predicts risk for mortality. Mechanistic studies in chronic stress models suggest that prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal medullary (SAM) axis may promote cancer progression. Our recent work has shown that environmental enrichment (EE), a housing environment boosting mental health, inhibits tumor growth by activating the hypothalamic- sympathoneural-adipocyte (HSA) axis. The stimulations provided in EE stimulate brain- derived neurotrophic factor (BDNF) expression in the hypothalamus leading to preferential sympathoneural activation of white fat. The elevated sympathetic drive activates adipocyte ss-adrenergic receptors inhibiting leptin expression and release, and thereby suppresses cancer growth. In contrast, social isolation (SI) is linked to increased tumor burden. However, both EE and SI increase the classical stress hormones, glucocorticoids and catecholamines, and ss-adrenergic blockers may abrogate their effects on cancer. This apparent paradox may in part lie in the lack of recognition of the difference between "eustress" (positive stress) and "distress" (negative stress) and their opposing health outcomes. The long-term goal of this project is to understand how the eustressful and distressful events trigger distinct molecular changes in the brain leading to an orchestrated differential activation of the three neuroendocrine axes: HPA, SAM and HSA, and subsequent opposite influences on cancer. Specifically we propose to use a multidisciplinary approach to provide a comprehensive and explicit comparison between the eustress model EE versus distress model SI on cancer progression, metabolism, and fat physiology. The analysis of the nature and magnitude of the 3 axes will help to elucidate the mechanisms underlying eustress-associated anticancer versus distress-associated pro- cancer phenotype. In addition we plan to profile the gene expression in the laser-capture microdissected hypothalamus nuclei to identify molecular mediators distinguishing eustress and distress. Furthermore we will investigate the role of hypothalamic BDNF in mediating SI impact on cancer. These studies may reveal novel therapeutic targets for cancer prevention and treatment.

Public Health Relevance

Cancer is influenced by physical and social environments with social support linked to improved health outcomes among cancer patients whereas social isolation predicts risk for mortality. The purpose of this project is to understand how the differet environmental events trigger distinct molecular changes in the brain leading to anti-cancer or pro-cancer effects, and to identify molecular mediators distinguishing eustress (positive stress) and distress (negative stress), which may reveal novel therapeutic targets for cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163640-02
Application #
8641669
Study Section
Special Emphasis Panel (ZRG1-BBBP-V (05))
Program Officer
Mc Donald, Paige A
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$227,248
Indirect Cost
$79,565
Name
Ohio State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Liu, Xianglan; Magee, Daniel; Wang, Chuansong et al. (2014) Adipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype. Mol Ther Methods Clin Dev 1: