Assessing the impact of WTC dust exposure on prostate cancer recurrence

项目总结 该应用程序通过与世界卫生组织的合作研究协议解决有针对性的健康问题 贸易中心(WTC)健康计划(UO1)。WTC中致癌物和致炎诱导物的存在 粉尘增加了9/11袭击期间接触世贸中心粉尘的人可能增加的可能性 癌症发病率。到目前为止，几项队列研究表明，总的癌症发病率比背景高出6-14% 甲状腺癌和前列腺癌的发病率显著增加(Moir，2016；Solan，2013；Li，2012； 约旦，2011年；Zeig-Owens，2011年)。 根据工人到达的时间、他们对WTC的早期反应的接近程度以及 暴露时间与肿瘤进展的风险增加有关(De la Hoz，2008；Lioy和 乔治波洛斯，2006)。最近在小动物模型中的研究表明，WTC尘埃颗粒或金属是 在WTC粉尘后，与肺相比，前列腺组织中检测不到或存在极低的水平 通过吸入或灌胃暴露(Wang，2022；Gong，2019)，对啮齿动物的长期研究尚未揭示 直接致癌机制的证据。相反，有证据表明，人类RNA表达和 DNA甲基化分析(Yu，2022)和炎症诱导的动物模型(Wang，2022；Gong，2019) 这种粉尘可能与前列腺癌的发生有关。在小鼠中，WTC粉尘暴露促进 全身性和局限性前列腺炎，PTEN缺陷的前列腺上皮生长增加和 促进基因起源的前列腺癌(Wang，2022)。 目标1将调查WTC相关前列腺癌是否更有可能独立于肿瘤而复发 在诊断时进行分级，以及复发者在诊断时是否有侵袭性的分子特征。我们 将利用增加的生化(PSA)复发来定义对WTC有不良临床反应的应答者 手术或放射治疗后的灰尘。我们还将通过RNA表达应用最近识别的签名 对前列腺癌组织进行分析和质谱仪多重免疫染色，以测试这些 免疫/炎症标志物与WTC应答者肿瘤复发增加相关。 目标2将专注于将我们的人类发现与小鼠基因工程小鼠模型的发现相关联 对前列腺癌进行靶向损伤，以模拟人类PC。这些实验利用了我们强大的 初步证据表明，这些模型支持WTC粉尘暴露在PC进展中的作用。实验 将包括测试WTC粉尘暴露是否促进以下遗传性PC的复发 雄激素剥夺治疗和/或实验性PC转移。我们还将比较和对比WTC尘埃 小鼠的免疫/炎症生物标记物与人类PC中识别的生物标记物相关联。 我们的首要目标是将所获得的理解转化为改善对WTC响应者的监督 最有可能患前列腺癌的人。

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.