214 High fat diet accelerates UVB-induced development of basal cell and squamous cell carcinoma in Ptch+/-/SKH-1 mice

Abstract

Squamous cell (SCC) and basal cell carcinomas (BCC), known as nonmelanoma skin cancers (NMSC), are the most commonly diagnosed human neoplasms in the United States. High-fat diet (HFD) is strongly associated with the risk of many cancer types, including skin cancers. Here, we showed that UVB-irradiated Ptch1+/-/SKH-1 hairless mice fed with HFD had earlier cutaneous tumor incidence and greater tumor burden (p<0.01) than control, normal diet (ND)-fed mice. We analyzed tumor samples using immunohistochemistry (IHC), Western blot, and microarray for various biomarkers. These data show that HFD enhanced the growth of tumors associated wtih high expression of the proliferation biomarkers PCNA and cyclin D1. Furthermore, activation of MAP kinase and PI3K/AKT pathways were also elevated more frequently in tumor tissues of mice fed with HFD. An Inflammatory Cytokines & Receptors RT2 Profiler PCR Array showed that expression of 24 of 84 genes was increased and 22 decreased in HFD-fed murine skin compared to ND. HFD further increased expression of 16 inflammation-related genes in UVB-irradiated nontumor skin tissue. Additionally, we observed augmented recruitment of myeloid-derived suppressor cells (CD11b/GR1-positive) in UVB-irradiated dermis and tumor stroma of HFD mice. We also found increased epithelial-to-mesenchymal transition, depictive of tumor invasiveness, in tumor tissues of UVB-irradiated HFD mice versus control. This was evident through reduced expression of epithelial marker E-cadherin, and increased expression of mesenchymal markers snail, twist, slug, and vimentin. In summary, our findings show that HFD augments UVB-induced carcinogenesis through recruitment of inflammatory cells and enhancement of aggressive tumor phenotypes.