Assessing the impact of WTC dust exposure on prostate cancer recurrence

PROJECT SUMMARY
This application addresses targeted health issues through a Cooperative Research Agreement with the World
Trade Center (WTC) Health Program (UO1). The presence of carcinogens and inducers of inflammation in WTC
dust have raised the possibility that those exposed to WTC dust during the 9/11 attacks could have increased
cancer incidence. To date, several cohort studies indicate that total cancer rates are 6-14% above background
rates with significantly greater increases for thyroid and prostate cancer (Moir, 2016; Solan, 2013; Li, 2012;
Jordan, 2011; Zeig-Owens, 2011).
Increased exposure based on the time of arrival for workers, their proximity to early response to the WTC and
duration of exposure have been associated with increased risk of tumor progression (de la Hoz, 2008; Lioy and
Georgopoulos, 2006). Recent studies in small animal models indicate that WTC dust particles or metals are
undetectable or present at exceedingly low levels in prostate tissues compared to lung following WTC dust
exposure by inhalation or gavage (Wang, 2022; Gong, 2019), and long-term studies of rodents have not revealed
evidence of a direct carcinogenic mechanism. Instead, there is evidence from both human RNA expression and
DNA methylation analyses (Yu, 2022) and animal models (Wang, 2022; Gong, 2019) that inflammation induced
by this dust may be implicated in promoting prostate cancer. In the mouse, WTC dust exposure promotes
systemic as well as localized prostate inflammation, increased growth in PTEN deficient prostate epithelia and
promotion of genetically initiated prostate tumors (Wang, 2022).
Aim 1 will investigate whether WTC associated prostate cancer is more likely to recur independent of tumor
grade at diagnosis and if there are molecular signatures of aggressiveness at diagnosis in those who recur. We
will utilize increased biochemical (PSA) recurrence to define responders with adverse clinical response to WTC
dust following surgery or radiation therapy. We will also apply recently identified signatures by RNA expression
analysis and mass spec multiplex immunostaining of primary prostate cancer tissues to test whether these
immune/inflammatory markers correlate with increased tumor recurrence in WTC responders.
Aim 2 will focus on correlating our human findings with those in mouse genetically engineered mouse models
bearing targeted lesions to prostate that model human PC. These experiments take advantage of our strong
preliminary evidence that these models support a role of WTC dust exposure in PC progression. Experiments
will include testing whether WTC dust exposure promotes recurrence of genetically initiated PCs following
androgen deprivation therapy and/or experimental PC metastasis. We will also compare, and contrast WTC dust
associated immune/inflammatory biomarkers in the mouse with those identified in human PCs.
Our overarching goal is to translate understanding gained toward improved surveillance of WTC responders
most at risk for prostate cancer.

Grant Number: 5U01OH012628-03
NIH Institute/Center: ALLCDC
Principal Investigator: Stuart Aaronson