Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1-/-) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1-/- mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1.

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Inflammation is a key component of cancer development in many tissues. Emerging clinical observations support the idea of a strong association of chronic inflammation and cancer. The JAK-STAT pathway is one of the major signaling pathways involved in modulating both pro- and anti-inflammatory responses. Aberrant expression of STATs has been reported in multiple human cancers and in animal models of tumorigenesis. Previous work performed in our lab demonstrated a role for Stat1 in mediating the promotion stage of epithelial multi-stage carcinogenesis in mouse skin when chrysarobin was used as the promoting agent. To further investigate the role of Stat1 in chrysarobin-mediated skin tumor promotion, Stat1 knockout (KO) mice and wild-type controls were treated with chrysarobin and the inflammatory response was assessed. Stat1 deficiency caused a reduction in the dermal inflammatory response following a single topical application of chrysarobin. In this regard, Stat1 KO mice had reduced dermal immune cell influx following chrysarobin treatment. In particular, Stat1 KO mice exhibited reduced influx of macrophages following a single application. Other results also suggest that Stat1 may regulate various cytokine/chemokines involved in the inflammatory response following chrysarobin treatment. Mice deficient in Stat1 displayed an attenuated induction of Cox-2 mRNA and protein compared to wild-type controls following a single application of chrysarobin (200 nmol per mouse). This latter data suggest that Stat1 may be involved in the regulation of Cox-2 in keratinocytes. Collectively, these findings suggest that Stat1 may contribute to chrysarobin-mediated skin tumor promotion by regulating, in part, levels of Cox-2, PGE2 and ultimately skin inflammation. These and other ongoing studies aimed at identifying the mechanistic basis for the role of Stat1 in chrysarobin-mediated tumor promotion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2011-2730