This research proposes to investigate our interesting findings of high scientific and medical significance involving colonic malignancies that are common and deadly in human patients. In humans, inflammation is a well-recognized risk factor for cancer. We have shown in mice that supplementation with anti-inflammatory CD4+ regulatory cells (Treg) which promote immune homeostasis in the lower bowel are highly effective in preventing and treating colonic cancers. However, high levels of inflammatory factors within the tumor microenvironment may create a vicious cycle that undermines protective functions of Treg. Thus, strategies that enhance potency of Treg to maintain homeostasis and constructively down-regulate inflammation may be of great value in fighting cancer. A recent and repeatable finding in our lab relates to the well-regarded 'hygiene hypothesis'in that prior exposures to enteric bacteria appear to enhance potency of Treg to protect against cancer. We propose to test immune strategies that optimize the intestinal balance between bacteria, inflammatory cytokines and Treg. We speculate that targeted stimulation of beneficial Treg using oral vaccination strategies may ultimately provide population-based approaches to abolish inflammation-associated cancers in humans.

Public Health Relevance

Chronic inflammation increases risk of cancer in humans and in mice. Anti-inflammatory regulatory T cells (Treg) normally function to maintain immune balance and down- regulate inflammatory factors that lead to cancer growth. We propose to build upon our recent scientific breakthroughs and test strategies in mice that will stimulate potent and highly beneficial Treg to prevent cancer and impart healthful longevity in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108854-08
Application #
8433461
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Daschner, Phillip J
Project Start
2004-07-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2013
Total Cost
$293,763
Indirect Cost
$110,278
Name
Massachusetts Institute of Technology
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Erdman, S E; Poutahidis, T (2014) Probiotic 'glow of health': it's more than skin deep. Benef Microbes 5:109-19
Poutahidis, Theofilos; Springer, Alex; Levkovich, Tatiana et al. (2014) Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice. PLoS One 9:e84877
Lakritz, Jessica R; Poutahidis, Theofilos; Levkovich, Tatiana et al. (2014) Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice. Int J Cancer 135:529-40
Levkovich, Tatiana; Poutahidis, Theofilos; Smillie, Christopher et al. (2013) Probiotic bacteria induce a 'glow of health'. PLoS One 8:e53867
Poutahidis, Theofilos; Cappelle, Kelsey; Levkovich, Tatiana et al. (2013) Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice. PLoS One 8:e73933
Poutahidis, Theofilos; Kearney, Sean M; Levkovich, Tatiana et al. (2013) Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One 8:e78898
Poutahidis, Theofilos; Kleinewietfeld, Markus; Smillie, Christopher et al. (2013) Microbial reprogramming inhibits Western diet-associated obesity. PLoS One 8:e68596
Fox, J G; Ge, Z; Whary, M T et al. (2011) Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. Mucosal Immunol 4:22-30
Yang, Huei-Ting; Wang, Yanyan; Zhao, Xixing et al. (2011) NF-*B1 inhibits TLR-induced IFN-* production in macrophages through TPL-2-dependent ERK activation. J Immunol 186:1989-96
Houghton, JeanMarie; Li, Hanchen; Fan, Xueli et al. (2010) Mutations in bone marrow-derived stromal stem cells unmask latent malignancy. Stem Cells Dev 19:1153-66

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