Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our recent work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, lower leptin level, higher adiponectin level, enhanced immune functions, and marked inhibition in melanoma and colon cancer growth. One key underlying mechanism is the activation of the hypothalamic- sympathoneural-adipocyte (HSA) axis whereby the physical, social and cognitive 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. The long-term goal of this project is to further characterize the role of HSA axis in cancer development and progression. Specifically we propose to generalize HSA activation to additional cancer models particularly the cancers with the strongest association with obesity such as breast cancer, and evaluate its long-term preventive effects. In addition we plan to determine whether genetically activating HSA axis by BDNF gene therapy can alleviate obesity and inhibit tumor growth in melanocortin receptor 4 (MC4R) deficient mice. Moreover we will evaluate whether long-term BDNF gene therapy using an autoregulatory vector can prevent the premature mortality in MC4R mice, a model representing the most common monogenic form of obesity. These studies will further characterize the HSA axis, elucidate underlying mechanisms, identify potential therapeutic targets, and provide the preclinical data to assess the potential to ultimate clinical intervention for cancer.

Public Health Relevance

Our recent work has shown that the environmental or genetic activation of a brain-fat axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis, leads to an anti-obesity and anti- cancer phenotype. The purpose of this project is to study the preventive and therapeutic effects of HSA activation in several clinical relevant models and to further elucidate the underlying mechanisms with the ultimate goal of utilizing this knowledge to develop interventions for cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166590-02
Application #
8594234
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Malone, Winfred F
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$287,128
Indirect Cost
$100,378
Name
Ohio State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
McMurphy, Travis; Xiao, Run; Magee, Daniel et al. (2014) The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma. PLoS One 9:e89895
Liu, Xianglan; McMurphy, Travis; Xiao, Run et al. (2014) Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice. Mol Ther 22:1275-84
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: