Abstract 2911: Intersection of aging, the microbiome and inflammation in a mouse model of bladder cancer
Authors: Woolbright Benjamin L. , Abbott Erika , Rajendran Ganeshkumar , Zhong Cuncong , Xuan Hao , Umar Shahid , Taylor John Arthur 
Published: July 2021

Abstract
Bladder cancer (BCa) is a disease strongly related to aging and remains a major source of morbidity and mortality in the elderly. Older patients are at greater risk of developing BCa and treatment outcomes remain poor. Interventions aimed at delaying recurrence and enhancing therapy would be highly beneficial given the aging US population and association with BCa. Aging is associated with baseline immune dysfunction, increasing risk for chronic diseases such as cancers. Compounding this issue, dysregulated inflammation in cancer results in a switch in the inflammatory milieu toward a pro-tumorigenic phenotype. Recent studies have indicated immune dysregulation in multiple cancers is also likely related to the changes in the underlying microbiome. The impact of age-related changes in the microbiome and inflammatory status, and how this relates to progression of tumorigenesis in the bladder have not yet been defined though. We hypothesized aging would enhance inflammation and carcinogenesis in a mouse model of carcinogen induced BCa. To determine how aging affects BCa, we exposed middle aged mice (14 months old at study start), and young mice (2 months old at study start) to the urothelial carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) 0.05% in drinking water for 6-20 weeks. Pathological analysis indicated older mice had higher indices of cellular inflammation at baseline and after BBN. Similarly, older mice had significantly more upregulation of pro-inflammatory mediators after 6 weeks exposure to BBN. While inflammatory metrics were increased, this did not extend to tumor size or stage. Middle aged mice (14 months) do not express prototypical biomarkers of aging yet though, and represent a very mild phenotype. To test the idea that truly older mice would be more susceptible to carcinogenesis, we treated young mice (8 weeks at start) or truly old mice (18 months at start) with 0.05% BBN for 16 weeks. We found older animals had larger tumors indicative of increased tumorigenesis after 16 weeks BBN. Moreover, multiple older mice muscle invasive tumors which were absent in the young group and increased recruitment of neutrophils indicative of increased inflammation. We subsequently analyzed the fecal microbiome using 16S sequencing of bacterial DNA. ß-diversity indices indicated substantial differences in microbiota constituency between young and older mice with cancer, although these differences were not observed at baseline. Future goals are to determine if aging-related alterations in the microbiome are responsible for the observed changes in tumor formation and inflammation. In conclusion, aged animals experience more inflammation, major changes in gut microbial content, and develop larger and more aggressive tumors after exposure to carcinogens implicating a pathological role for aging in BCa.
Citation Format: Benjamin L. Woolbright, Erika Abbott, Ganeshkumar Rajendran, Cuncong Zhong, Hao Xuan, Shahid Umar, John Arthur Taylor. Intersection of aging, the microbiome and inflammation in a mouse model of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2911.