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（由申请人提供）：美国每年进行 1,300,000 次前列腺活检，检测出约 218,000 例前列腺癌新病例。此外，这些前列腺活检每年识别出 115,000 例无癌症的前列腺上皮内瘤变 (PIN) 独立病例，约占总病例的 9%。 PIN 在 20 世纪 60 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和腺泡，内衬细胞学非典型细胞，并细分为低级 (LGPIN) 和高级 PIN (HGPIN)。 PIN 的临床意义在于其作为前列腺癌诊断标志物的预测价值。然而，研究表明，HGPIN 病变的某些部分可以保持在癌前阶段，不会进展为前列腺癌，而其他部分则进展为疾病进展。这些差异使我们无法做出早期准确的诊断并为患者提供即时有效的治疗。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的细胞特性及其可促进 PIN 致癌进展为前列腺癌的分子决定因素。 通过雄激素受体 (AR) 及其配体睾酮和 5-氢睾酮 (DHT) 介导的雄激素信号通路对于前列腺癌的发生和进展至关重要。研究表明，雄激素途径的失调直接导致前列腺癌转化和从 PIN 发展为前列腺癌。有趣的是，雄激素消融可以显着降低 PIN 病变的发生率和范围，这表明 PIN 病变中非典型细胞的生长完全依赖于雄激素。这一结果还意味着雄激素消融疗法可以抑制 PIN 进展，并可能在预防和减少男性前列腺癌方面具有临床应用。然而，雄激素信号传导异常激活在 PIN 启动过程中诱导致癌转化中的确切作用尚不清楚。这也是 目前尚不清楚为什么某些 PIN 病变能够进展为前列腺癌，而其他病变仍处于“癌前状态”。在这个新的 R21 应用中，我们将使用我们新的 AR 转基因小鼠模型 R26hARL/wt;Osr1-Cre 小鼠来测试我们的中心假设，即雄激素信号传导的异常激活直接导致 PIN 的启动和进展，因此抑制雄激素信号传导可以抑制 PIN 的发育并防止其进展为前列腺腺癌。提出了两个具体目标来解决两个重要问题：1）PIN 的启动和进展是否完全依赖于雄激素？雄激素消融能否预防 PIN 恶性进展为前列腺癌？ 2) PIN 病变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 PIN 启动和致癌进展？