People with cancer abuse alcohol. While 20% w/v alcohol consumed in the drinking water generally suppresses the immune response paradoxically decreases metastasis of murine B16BL6 melanoma, a very invasive and metastatic cell line. Interferon gamma (IFN-gamma) produced by natural killer (NK) and NKT cells and possibly memory T cells is essential to control metastasis of melanoma. Preliminary data indicate that alcohol consumption significantly increases the percentage of NKT cells in the periphery and the percentage of IFN-gamma producing NKT and T memory cells to reduce metastasis. Alcohol consuming mice die prematurely even though metastasis is inhibited and the mechanisms associated for this decrease in survival will be investigated. Thus, it is hypothesized that the antimetastatic effect of chronic alcohol consumption is due to increased production of IFN-gamma by NKT and memory T cells. It is further hypothesized that alcohol consumption decreases survival through a combination of effects on altering T cell survival, hypoglycemia, and oxidative stress. To test these hypotheses, we propose the following specific aims: 1. Determine the contributions of NKT cells and T cells to the mechanism by which alcohol consumption inhibits melanoma metastasis 2. Determine the effect of alcohol on metastasis of other animal tumor models. 3. Determine the mechanisms associated with decreased survival of alcohol consuming, melanoma-bearing mice. Alcohol will be fed to female C57BL/6, NKT knockout, IFN-gamma knockout, and nude mice to assess the mechanisms associated with inhibition of melanoma metastasis. Experimental and spontaneous metastasis assays also will examine metastasis of RM-1 prostate cancer and 3LL Lewis lung carconima in appropriate alcohol- consuming murine models. Flow cytometric and ELISA assays will be used to determine lymphocyte populations, surface and intracellular marker expression, cytokine producing cells, and cytokine concentrations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007293-20
Application #
7845553
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Jung, Kathy
Project Start
1987-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
20
Fiscal Year
2010
Total Cost
$317,514
Indirect Cost
Name
Washington State University
Department
Internal Medicine/Medicine
Type
Schools of Pharmacy
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Meadows, Gary G (2012) Diet, nutrients, phytochemicals, and cancer metastasis suppressor genes. Cancer Metastasis Rev 31:441-54
Zhang, Hui; Zhu, Zhaohui; Meadows, Gary G (2012) Chronic alcohol consumption impairs distribution and compromises circulation of B cells in B16BL6 melanoma-bearing mice. J Immunol 189:1340-8
Powers, John; Zhang, Hui; Battrell, Logan et al. (2012) Establishment of an immunodeficient alcohol mouse model to study the effects of alcohol on human cells in vivo. J Stud Alcohol Drugs 73:933-7
Vorderstrasse, Beth A; Wang, Tao; Myers, Annette K et al. (2012) Alcohol consumption suppresses mammary tumor metastasis in a syngeneic tumor transplantation model. Breast Cancer Res Treat 136:729-37
Zhang, Xingqi; Lan, Ni; Bach, Paxton et al. (2012) Prenatal alcohol exposure alters the course and severity of adjuvant-induced arthritis in female rats. Brain Behav Immun 26:439-50
Wang, Tao; Wyrick, Katie L; Meadows, Gary G et al. (2011) Activation of the aryl hydrocarbon receptor by TCDD inhibits mammary tumor metastasis in a syngeneic mouse model of breast cancer. Toxicol Sci 124:291-8
Zhang, Hui; Zhu, Zhaohui; Meadows, Gary G (2011) Chronic alcohol consumption decreases the percentage and number of NK cells in the peripheral lymph nodes and exacerbates B16BL6 melanoma metastasis into the draining lymph nodes. Cell Immunol 266:172-9
Zhang, Hui; Zhu, Zhaohui; McKinley, Jenifer M et al. (2011) IFN-? is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice. Clin Exp Metastasis 28:301-7
D'Souza El-Guindy, Nympha B; Kovacs, Elizabeth J; De Witte, Philippe et al. (2010) Laboratory models available to study alcohol-induced organ damage and immune variations: choosing the appropriate model. Alcohol Clin Exp Res 34:1489-511
Zhang, Hui; Meadows, Gary G (2010) Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice. Cancer Immunol Immunother 59:1151-9

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