Elucidating and testing causal drivers of inflammation triggered prostatic early lesions

项目摘要/摘要： 我们认为人PIA中的炎性浸润物反映了一种抗前列腺癌的促炎免疫。 作为启动癌症的温床的反应。有趣的是，急性和慢性炎症细胞 PIA中常见的浸润性病变通常在大多数前列腺癌中看不到。这些观察结果促使人们 我们的试验场假说表明，为了使前列腺癌发展到超过这些阶段 在PIA中启动的步骤是真正的前肿瘤前体(PIN)和浸润性癌，这种免疫 必须废除回应。我们观察到人类应激反应和炎症基因的上调。 Pia腔上皮细胞。这些相同的基因(例如：GSTP1、Ptgs2和LTf)在表观遗传上是沉默的 在PIN和早期和转移性前列腺癌中。这导致了一种潜在的分子 在PIA中被高度诱导表达的一组基因经历沉默以允许细胞 表现为PIN和浸润性癌。我们在这里表明，主要的炎症介质刺激因子 干扰素基因(STING)在正常前列腺腔细胞中缺失，在中腔细胞中高度诱导 细胞在PIA中表达，而在绝大多数人PIN和腺癌中不表达。我们假设 炎症、细胞损伤和前列腺癌的发生都需要在PIA腔细胞中表达STING。 其次，我们假设在PIA细胞的一个子集中，STIN(或其下游)的表观遗传沉默 信号活动)导致免疫反应减弱，通过允许它们产生生长优势 以肿瘤细胞的形式出现。我们将在以下方面检验这些假设。在特定的目标1中，我们将从基因上 并从药理学上验证了刺痛激活假说对急性和慢性炎症的影响 使用我们独特的IL1-β诱导的前列腺炎小鼠模型和PIN在小鼠前列腺中的表达 PIA进展为PIN(IMPI小鼠)。在特定目标2中，我们将测试“诱导基因的表观遗传沉默”。 通过对基于DNA甲基化的人类样本进行全面表征来实现假说 前列腺炎性病变向前列腺癌转化过程中小鼠和人上皮细胞的表观基因组学变化 肿瘤。从机制上讲，我们假设刺痛(与许多其他应激和炎症一起引起 基因)在PIA向高级别PIN的过渡阶段表观遗传沉默。在具体目标3中，我们 假设在从试验场“毕业”的过程中，肿瘤细胞留下了促炎因子 PIA的微环境，塑造一个适应性免疫细胞减少的微环境 免疫抑制髓系细胞和淋巴样细胞(如MDSCs、M2巨噬细胞和Tregs)的招募 帮助平息癌症免疫反应。我们将定义的细胞组成和空间架构 小鼠和人早期前列腺炎性病变的微环境。

Project Summary/Abstract: We have proposed that inflammatory infiltrates in human PIA reflect an anti-prostatic pro-inflammatory immune response that serves as a hotbed for cancer initiation. Interestingly, the acute and chronic inflammatory cell infiltrates common in PIA are generally not seen in most prostate cancers. These observations have prompted our proving ground hypothesis which suggests that in order for prostate cancer to develop past these initiated steps in PIA to bona fide pre-neoplastic precursor (PIN) and to invasive carcinoma, this immune response must be abrogated. We observed upregulation of stress-response and inflammatory genes in human PIA luminal epithelial cells. These same genes (examples: GSTP1, PTGS2, and LTF ) are epigenetically silenced in PIN and early and metastatic invasive adenocarcinoma of the prostate. This led to a potential molecular mechanism in which a set of genes whose expression is highly induced in PIA undergo silencing to allow cells to emerge as PIN and invasive carcinoma. We show here that the major inflammatory mediator Stimulator of Interferon Genes (STING) is absent in normal prostate luminal cells, is highly induced in intermediate luminal cells in PIA, and is not expressed in the vast majority of human PIN and adenocarcinomas. We hypothesize STING expression in PIA luminal cells is required for inflammation, cell injury, and the prostate cancer initiation. Second, we hypothesize that in a subset of PIA cells, epigenetic silencing of STING (or of its downstream signaling activity) results in dampening of the immune response, imparting a growth advantage by allowing them to emerge as neoplastic cells. We will test these hypotheses in as follows. In Specific Aim 1 we will genetically and pharmacologically test the STING activation hypothesis for developing acute and chronic inflammation, PIA and PIN in the mouse prostate using our unique mouse model of IL1-beta induced prostatic inflammation and PIA progressing to PIN (IMPI mice). In Specific Aim 2 we will test the “epigenetic silencing of induced genes” hypothesis in human samples by performing a comprehensive characterization of DNA-methylation based epigenomic changes in mouse and human epithelial cells in the transitions from prostatic inflammatory lesions to neoplasia. Mechanistically, we hypothesize that STING (along with many other stress and inflammation induced genes) is epigenetically silenced at the transition stage of PIA to high grade PIN. In Specific Aim 3, we hypothesize that in "graduating" from the proving ground, neoplastic cells leave behind the pro-inflammatory microenvironment in PIA, and sculpt a microenvironment with reduced adaptive immune cells through recruitment of immune suppressive myeloid and lymphoid cells (e.g. MDSCs, M2 macrophages and Tregs) that help quell the cancer immune response. We will define the cellular composition and spatial architecture of microenvironment in mouse and human early precursor prostatic inflammatory lesions.