Date of Graduation

12-2016

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Yi Xu

Committee Member

Magnus Hook

Committee Member

Scott Kopetz

Committee Member

Barbara Murray

Committee Member

Dekai Zhang

Abstract

Colorectal cancer (CRC) is the third most common cancer in men and women and is also the third most common cause of cancer death. A large body of evidence points towards the possibility that bacteria can have a significant impact on the development of cancer. It has been suggested that Streptococcus gallolyticus subsp. gallolyticus, a group D streptococci, may play a role in the development of CRC. Sg, formerly S. bovis biotype I, has been shown to be highly associated with CRC. In observing patients with either Sg bacteremia or endocarditis it was found that 25-80% of patients with Sg bacteremia had tumors and 18-62% of patients with Sg endocarditis had colonic neoplasias. However, other closely related Streptococcal strains, such as S. pasterianus and S. infantarius, have not been shown to have this strong association with CRC. In fact, it has been shown that biotype I is more often associated with CRC (94%) as compared to biotype II (18%). This knowledge has important clinical implications, and yet little is known about the role of Sg on CRC and the underlying mechanisms. Here we show that mice treated with Sg had significantly more tumors, higher tumor burden and dysplasia grade, and increased cell proliferation and β-catenin level in colonic crypts compared to mice treated with control bacteria. Sg strains that promoted proliferation were also more efficient at adhering to CRC cell lines and colonizing a mouse model. Additionally, in human patients Sg was highly prevalent in CRC patients and tumor tissues had an increased Sg burden in comparison to normal adjacent tissues. These results provide exciting new information and establish a tumor-promoting role of Sg that involves specific bacterial and host factors.

Keywords

Colorectal cancer, microbiome, Streptococcus gallolyticus, Streptococcus bovis, β-catenin, tumorigenesis

Available for download on Tuesday, December 12, 2017

Share

COinS