Abstract 695: Exposure to World Trade Center (WTC) dust initiates a pro-cancer inflammatory signature in mice
Authors: Wang Lin , Kobryn Andriy , Kang Kyeongah , Taioli Emanuela , Oh William , Boffetta Paolo , Chen Shu-Hsia , Aaronson Stuart , Mulholland David J. 
Published: August 2018

Abstract
The World Trade Center destruction exposed many individuals to chemicals associated with inflammation and cancer including insulation fibers, asbestos, glass fibers and dioxins. Though the exposure to WTC dust was short, responders experienced an acute intake of harmful dust particles may be at risk for developing long term health problems. To date, responders have shown higher rates of prostate and thyroid cancer compared to non-exposed individuals. Curiously, rates of lung cancer have not shown to increase. To model the effects of WTC dust exposure on inflammation and cancer, we have taken a genetic approach including treatment of Wt C57/Bl6j mice and mice with genetic predisposition to prostate or lung cancer. Using a dosing strategy consisting of 4 consecutive exposures to WTC dust (3 mg/30 ul in PBS dosed via nasal instillation), we assayed for changes in immune and inflammatory gene expression at short term (7 days post exposure) and longer (3 wks. post exposure) time points. RNAs from normal prostate, spleen, lung and blood were assessed using RT2 Profiler PCR Arrays (Inflammation Panel). Organs harvested from WTC dust treated mice showed increased expression of markers including prostate (Ctla4, Cxcl5, IL17a, Il6), lung (Cxcl5, Cxcr1, Bcl2l1), spleen (Ccl20, Cxcl11, Ccl28, Il17a) and blood (Il6) when normalized to PBS controls. As an extreme test of WTC dust effects in a target organ, WTC dust was introduced directly to the mouse prostate (4 mg, orthotoptic injection), resulting in significantly increased prostate size associated with marked elevation of inflammatory/immune gene expression (Cxcl5, Il17a, Ccl20, Il6, Ifng). Histological analysis showed massive immune cell infiltration as well as increased proliferation of prostate epithelia (5-7% Ki67+) compared to PBS controls (0.1%). Collectively, these data indicate that WTC dust can induce a strong inflammatory response systemically or by contact with the cells of the prostate. To determine whether WTC dust exposure promotes cancer progression, we applied two genetically mouse (GEM) models of cancer susceptibility. These include use of prostate specific Cre recombinase (Probasin Cre), to induce susceptibility to prostate cancer by loss of function of key tumor suppressors (Ptenloxp/Wt, p53loxp/Wt) or activation of oncogenes (Krasloxp-G12D) but also to induce cancer susceptibility in lung in a GEM model with Adeno cre virus mediated excision of p53loxp/Wt and KrasG12D. These studies indicate that WTC dust exposure is capable of inducing a strong inflammatory response in mice including elevated expression of multiple cytokines that are associated with human cancer progression. Current studies will determine whether WTC dust exposure can induce cancer or promote progression in responders with or without genetic susceptibility to tumorigenesis.
Citation Format: Lin Wang, Andriy Kobryn, Kyeongah Kang, Emanuela Taioli, William Oh, Paolo Boffetta, Shu-Hsia Chen, Stuart Aaronson, David J. Mulholland. Exposure to World Trade Center (WTC) dust initiates a pro-cancer inflammatory signature in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 695.