World Trade Center Dust Exposure Promotes Cancer in PTEN-deficient Mouse Prostates

Abstract

During the 9/11 attacks, individuals were exposed to World Trade Center (WTC) dust which contained a complex mixture of carcinogens. Epidemiologic studies have revealed the increased incidence of prostate and thyroid cancer in WTC survivors and responders. While reports have shown that WTC-dust associates with the increased prevalence of inflammatory-related disorders, studies to date have not determined whether this exposure impacts cancer progression. In this study, we have used genetically engineered mouse (GEM) models with prostate-specific deletion of the PTEN tumor suppressor to study the impact of WTC-dust exposure on deposition of dust particles, inflammation, and cancer progression. In normal C57/BL6 mice, dust exposure increased cellular expression of inflammatory genes with highest levels in the lung and peripheral blood. In normal and tumor-bearing GEM mice, increased immune cell infiltration to the lungs was observed. Pathologic evaluation of mice at different timepoints showed that WTC-dust exposure promoted PI3K-AKT activation, increased epithelial proliferation and acinar invasion in prostates with heterozygous and homozygous Pten loss. Using autochthonous and transplant GEM models of prostate cancer, we demonstrated that dust exposure caused reduced survival as compared with control cohorts. Finally, we used imaging mass cytometry to detect elevated immune cell infiltration and cellular expression of inflammatory markers in prostate tumors isolated from human WTC survivors. Collectively, our study shows that chronic inflammation, induced by WTC dust exposure, promotes more aggressive cancer in genetically predisposed prostates and potentially in patients. Significance: We provide the first evidence that exposure to WTC dust promotes prostate cancer progression. These data may impact the diagnoses, clinical management, and treatment of responders who have or will develop cancer.