772 Age-associated alterations in pro-inflammatory cytokine signaling as well as UV-induced DNA damage contribute to increased basal cell carcinoma (BCC) tumor burden in Ptch1+/-/SKH-1 mice

Abstract

Human BCC incidence is age-dependent. We have developed Ptch1+/-/SKH-1 mice as a model of human BCC pathogenesis. These mice progressively develop spontaneous BCCs, suggesting per se age-related effects on cancer induction irrespective of aberrant hedgehog signaling. Here, utilizing cohorts of young (2 months) and aged (> 20 months) mice, we tested the hypothesis that chronologically aged skin is more susceptible to ultraviolet radiation (UVR)-induced skin damage and BCC growth as compared to young adult skin. UVR-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs) were measured in genomic DNA isolated from skin tissues at 24, 48, and 72h post-irradiation (240 mJ/cm2, single exposure). CPD levels peaked at 24h, decreasing gradually and were virtually undetectable after 72h in all cohorts, irrespective of age and sex. A similar pattern was observed for UV-induced 6-4PP in young cohorts. In contrast, skin 6-4PP levels persisted in aged Ptch1+/-/SKH-1 mice, indicating age-related differences in DNA repair capacity. Moreover, circulating levels of inflammatory cytokines known to be altered in cancer and aging (IL1β, IL6, TNFα) were significantly elevated in both aged male and female Ptch1+/-/SKH-1 mice, as well as in UV-irradiated young cohorts. Aged Ptch1+/-/SKH-1 mice subjected to chronic UVR (180 mJ/cm2, 2x/week, 16 weeks) revealed statistically significant increases in tumor burden (UV-irradiated vs. non-irradiated aged cohorts), while we observed < 2-fold increase in BCC burden in UV-irradiated young cohorts vs. non-irradiated controls. These results demonstrate differential susceptibility to UVR-induced BCCs in young and aged Ptch1+/-/SKH-1 mice such that aging enhances BCC burden in Ptch1-deficient skin, and altered DNA damage responses and systemic pro-inflammatory cytokine signaling may contribute to age-dependent enhancement of BCC tumorigenesis in human populations.