Age increases the expression of inflammatory genes in a mouse model of bladder cancer
John A. Taylor, III, MD, Shilpa Choudhary, -, George A. Kuchel, MD, Benjamin Ristau, MD, Olga S. Voznesensky, Poornima Hegde, MD, Carol Pilbeam, PhD, MD.
University of Connecticut, Farmington, CT, USA.
Introduction and Objective: Bladder cancer is predominantly a disease of old age. The relative risk of developing invasive disease rises sharply after the 7th decade of life. Inflammatory cytokines have been shown to play a potential role in the pathogenesis of bladder cancer and have been reported to increase with age suggesting a possible mechanism for this increased risk. We explored the impact of age on the expression of inflammatory genes in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer.
Methods: Young (3 months) and old (14-17 months) male C57BL/6 mice were given vehicle or BBN 0.05% in drinking water (n=4-9/group) for 20 weeks. Animals were euthanized at 6, 12 and 20 weeks with bladders harvested. Half of each bladder was used for histology and half for mRNA extraction. Expression levels for TNF-α, IL-6 and COX-2 were evaluated by quantitative real-time polymerase chain reaction (qPCR) with GAPDH as an endogenous control.
Results: At 20 weeks 5/9 young and 4/9 old animals had bladder cancer. No differences were seen in mRNA levels of studied cytokines in the young vs old vehicle treated mice at any time point. Treatment with BBN significantly increased the expression of all genes in both young and old animals. Higher levels were observed in the old relative to young BBN treated mice. COX-2 expression was elevated ~2-fold (p<0.01), IL-6 ~17-fold (p<0.01) at all time points and TNF-α ~1.5-2.4 - fold (p<0.01 at 12 weeks) in older mice relative to the increase seen in young animals after BBN treatment.
Conclusions: COX-2, TNF-α and IL-6 have been previously implicated in the development of bladder cancer. The response of these inflammatory genes to BBN was increased in older mice relative to young during development of tumor in the BBN mouse model of bladder cancer. Age-associated increase in expression of these genes may contribute to the increased risk of developing bladder cancer seen in the elderly.