Cellular And Molecular Properties Of PINs In Prostate Tumorigenesis

前列腺肿瘤发生中 PIN 的细胞和分子特性

• 批准号: 8791506
• 负责人: ZIJIE SUN
• 金额: $ 17.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791506
• 关键词: AR gene; Ablation; Acinus organ component; Address; Androgen Receptor; Androgens; Animal Model; Biological Markers; Biopsy; Cancerous; Castration; Cells; Chemicals; Data; Development; Diagnosis; Disease; Dysplasia; Event; Future; Growth; Healthcare Systems; Human; Lead; Lesion; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Mus; Oncogenic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Predictive Value; Premalignant; Prevalence; Property; Prostate; Prostate Adenocarcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic duct; Resources; Role; Signal Pathway; Signal Transduction; Staging; Stanolone; System; Testing; Testosterone; Therapeutic; Transgenes; Transgenic Mice; United States; Urogenital Sinus; advanced disease; cancer initiation; clinical application; clinically significant; cost; effective therapy; improved; in vivo; insight; men; mouse model; novel; novel therapeutics; prevent; prostate carcinogenesis; public health relevance; research study; tumor progression

DESCRIPTION (provided by applicant): There are 1,300,000 prostate biopsies performed annually that detect about 218,000 new cases of prostate cancer in the United States. Additionally, those prostate biopsies identify 115,000 independent cases of prostatic intraepithelial neoplasia (PIN) without cancer each year, representing about 9% of total cases. PIN was first described in the 1960s as ' intraductal dysplasia '. PIN features pre-existing prostatic ducts and acini lined by cytologically atypical cells, and are subdivided into low grade (LGPIN) and high grade PIN (HGPIN). The clinical significance of PIN is in its predictive value as a marker for diagnosis of prostate cancer. However, studies have shown that there are certain portions of HGPIN lesions that can remain in pre-malignant stages and do not progress to prostate cancer while others progress to advance disease. These discrepancies have prevented us from making early and accurate diagnosis and providing immediate and effective treatment for patients. They also result in significant unnecessary costs and negatively impact our healthcare system and economy. Therefore, there is an urgent need to investigate and define cellular properties of atypical cells and their molecular determinants that can promote PIN oncogenic progression to prostate cancer. The androgen signaling pathway, mediated through the androgen receptor (AR) and its ligands, testosterone and 5�ihydrotestosterone (DHT), is essential for prostate cancer initiation and progression. It has been shown that dysregulation of the androgen pathway directly contributes to prostatic oncogenic transformation and progression from PIN to prostate cancer. Intriguingly, androgen ablation can significantly reduce the prevalence and extent of PIN lesions, suggesting that the growths of atypical cells in PIN lesions are exquisitely androgen-dependent. This result also implies that androgen ablation therapy can inhibit PIN progression and may have a clinical application in preventing and reducing prostate cancer in men. However, the precise role for abnormal activation of androgen signaling in inducing oncogenic transformation during PIN initiation is largely unknown. It is also unclear why certain PIN lesions are able to progress to prostate cancer and others remain in "pre-malignant status". In this new R21 application, we will use our new AR transgenic mouse model, R26hARL/wt;Osr1-Cre mice to test our central hypothesis that abnormal activation of androgen signaling directly contributes to PIN initiation and progression and thus inhibition of androgen signaling can repress PIN development and prevent its progression to prostatic adenocarcinoma. Two specific aims are proposed to address two important questions: 1) Are PIN initiation and progression fully androgen-dependent and can androgen ablation prevent malignant progression of PIN to prostatic adenocarcinomas? and 2) What are the cellular and molecular properties of atypical cells in PIN lesions and how does abnormal activation of androgen signaling induce PIN initiation and oncogenic progression?

描述（由适用提供）：每年进行1,300,000个前列腺活检，在美国检测约218,000例新的前列腺癌病例。此外，这些前列腺活检确定了每年没有癌症的上皮内肿瘤（PIN）的115,000例独立的病例，约占总病例的9％。 PIN在1960年代首次被描述为“导管内发育不良”。 PIN具有预先存在的前列腺管道和由细胞学上非典型细胞衬里的ACINI，并细分为低级（LGPIN）和高级引脚（HGPIN）。 PIN的临床意义是其预测价值作为诊断前列腺癌的标志物。但是，研究表明，某些HGPIN病变可能会保留在恶性阶段，并且不会发展为前列腺癌，而其他人则进展发展为促进疾病。这些差异使我们无法尽早而准确的诊断，并为患者提供立即有效的治疗方法。它们还会导致大量不必要的成本，并对我们的医疗保健系统和经济产生负面影响。因此，迫切需要研究和定义非典型细胞及其分子确定剂的细胞特性，这些特性可以促进销育于前列腺癌的销育致癌性进展。通过雄激素受体（AR）及其配体，睾丸激素和5.Hydrototostosterone（DHT）介导的雄激素信号通路对于前列腺癌的启动和进展至关重要。已经表明，雄激素途径的失调直接导致前列腺致癌性转化和从PIN到前列腺癌的发展。有趣的是，雄激素消融可以显着降低引脚病变的患病率和程度，这表明销损伤中非典型细胞的生长完全依赖于雄激素。该结果还意味着雄激素消融疗法可以抑制销钉进展，并且可能在预防和减少男性前列腺癌方面具有临床应用。然而，在引入过程中，雄激素信号传导异常激活在诱导的致癌转化中的确切作用在很大程度上是未知的。也是 尚不清楚某些引脚病变能够进展到前列腺癌，而其他销钉处于“临时状态”。在此新的R21应用中，我们将使用我们的新AR转基因小鼠模型R26HARL/WT; OSR1-CRE小鼠来检验我们的中心假设，即异常激活雄激素信号直接激活直接有助于PIN启动和进展，从而抑制雄激素信号的发展，从而抑制PIN的发育并预防其前列腺症状腺瘤蛋白瘤。提出了两个具体的目的来解决两个重要问题：1）PIN启动和完全依赖雄激素的进展，并且雄激素消融是否可以防止PIN的恶性进展到前列腺腺癌？ 2）在销损伤中非典型细胞的细胞和分子特性是什么？雄激素信号传导的异常激活如何诱导销销和致癌进展？