Colorectal cancer (CRC) has a 5-year survival rate of 68% yet it still has a mortality rate of 50,000 per year. While CRC has a host of causes, one that stands out is TGFβ deficient signaling, which is disrupted in a majority of high-microsatellite-instability or inflammation-associated CRCs. Since TGFβ is a multifunctional cytokine, it has been elusive to determine whether its effect on cancer development is operating through inflammation, differentiation or developmental pathways. Additionally, it is now becoming apparent that a great number of CRC cases can be associated with and possibly caused by gut bacteria dysbiosis. Here, I present a metagenomic and metatranscriptomic study of the interactions between TGFβ deficient signaling, inflammatory signaling, and the microbiome in a CRC mouse model. TGFβ deficient mice have reduced amounts of Firmicutes as well as mRNA counts of a key butyrate enzyme. Lack of butyrate, as shown by previous literature, could be inhibiting apoptosis and promoting growth. Also, TGFβ deficient mice have increased mRNA counts of polyamine producing genes, which could act synergistically with butyrate reduction. I find that H. hepaticus inoculation, as a source of inflammatory signaling, affects another species, M. schaedleri, to produce pro- inflammatory lipopolysaccharides. Additionally, H. hepaticus itself has increased oxidative phosphorylation; reactive oxygen species from this process could be adding to cancer-promoting DNA damage. Taken together, TGFβ deficient signaling and H. hepaticus inoculation, disrupt enough pathways to cross the threshold of carcinogenicity in 40% of the mice in our study. The results of this study emphasize the importance of
microbiome function and represent possible new avenues of treatment.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/625592 |
| Date | January 2017 |
| Creators | Daniel, Scott Garrett, Daniel, Scott Garrett |
| Contributors | Hurwitz, Bonnie, Hurwitz, Bonnie, Buchan, John R., Yao, Guang, Doetschman, Thomas |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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