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The Effect of Inflammation on Stem Cell Mutagenesis and Carcinogenesis Induced by Azoxymethane in Wild type and Immune Compromised Mice

Whetstone, Ryan (2014) The Effect of Inflammation on Stem Cell Mutagenesis and Carcinogenesis Induced by Azoxymethane in Wild type and Immune Compromised Mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Colorectal cancer (CRC) is the third most prevalent cancer in men and women with almost 150,000 new cases diagnosed per year, and almost 50,000 deaths. Inflammation is recognized as a strong risk factor for CRC. The relationship between inflammation potentiating cancer remains unsettled although a common explanation for the role of inflammation involves the formation of reactive oxygen and nitrogen species (RONS). RONS can directly, through oxidation of DNA bases, or indirectly, through the formation of lipid peroxidation products, generate DNA lesions that in turn can lead to increased mutations that activate oncogenes and/or block the function of tumor suppressor genes. To address this fundamental question, C57Bl/6 (B6) WT and TCRβ null mice were treated with a DNA damaging agent (azoxymethane, AOM) and/or an inflammatory agent (dextran sulfate sodium, DSS) to mimic an inflammation model of CRC. The carcinogenic and mutagenic effect of the treatments was examined by pathological evaluation of the mouse colons and by measuring the somatic stem cell mutation frequency (MF) in the colon. The results of the carcinogenicity studies show that WT mice are more prone to development of CRC than the TCRβ-/- mice when a low concentration of DSS is used. The mutagenesis results find that DSS, which causes a strong inflammatory response, does NOT result in stem cell mutations in the colon of WT or TCRβ-/- mice. Therefore, inflammation does not potentiate cancer development by increasing the mutation rate. In contrast, AOM causes a significant increase in the colon stem cell MF in both strains but the MF is 50% lower in the TCRβ-/- vs. WT mice. Accordingly, we propose that the oncogenic mutations observed in CRC produced by the combination of a genotoxin with an inflammatory agent arise due to the transient creation of a mutator phenotype where stem cells with DNA damage are “forced” to bypass cell cycle arrest and apoptosis because of T-cell supported wound repair and tissue regeneration. We also propose that the effect of DSS treatments after AOM mutagenesis potentiates cancer development by dysregulation of intracellular levels of beta-catenin, thereby enhancing the oncogenic effects of AOM mutated beta-catenin.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Whetstone, Ryanrdw16@pitt.eduRDW16
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGold, Barrygoldbi@pitt.eduGOLDBI
Committee MemberEmpey, Kerry Mkme33@pitt.eduKME33
Committee MemberLi, Songsol4@pitt.eduSOL4
Committee MemberVollmer, Regis R.vollm@pitt.eduVOLLM
Committee MemberTurnquist, Hethhet5@pitt.eduHET5
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Date: 12 December 2014
Date Type: Publication
Defense Date: 20 November 2014
Approval Date: 12 December 2014
Submission Date: 12 December 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 230
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: azoxymethane dextran sulfate sodium mutagenesis colon carcinogenesis
Date Deposited: 12 Dec 2014 16:00
Last Modified: 19 Dec 2016 14:42


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