Cellular And Molecular Properties Of PINs In Prostate Tumorigenesis

描述(申请人提供)：美国每年进行130万例前列腺活检，发现约21.8万例前列腺癌新病例。此外，这些前列腺活检每年确定115,000例独立的无癌前列腺上皮内瘤变(PIN)病例，约占总病例的9%。上世纪60年代，PIN首次被描述为“导管内发育不良”。PIN以已存在的前列腺管和腺泡为特征，由细胞学上的非典型细胞排列，并分为低级别(LGPIN)和高级别(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的某些部分病变可能仍处于癌前阶段，不会进展为前列腺癌，而其他部分则进展为疾病。这些差异使我们无法及早做出准确的诊断，也无法为患者提供及时有效的治疗。它们还导致大量不必要的成本，并对我们的医疗体系和经济产生负面影响。因此，迫切需要研究和确定非典型细胞的细胞特性及其分子决定因素，以促进PIN向前列腺癌的致癌进展。雄激素信号通路通过雄激素受体(AR)及其配体--睾酮和5-羟基睾酮(5-�)介导，在前列腺癌的发生和发展中起重要作用。已有研究表明，雄激素途径的失调直接促进了前列腺癌从PIN向前列腺癌的转化和进展。有趣的是，雄激素消融可以显著降低PIN病变的患病率和程度，这表明PIN病变中非典型细胞的生长非常依赖雄激素。这一结果还表明，雄激素消融治疗可以抑制PIN的进展，并可能在预防和减少男性前列腺癌方面有临床应用。然而，雄激素信号的异常激活在PIN启动过程中诱导致癌转化的确切作用在很大程度上尚不清楚。它也是 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”。在这一新的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小鼠来验证我们的中心假设，即雄激素信号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可以抑制PIN的发育并防止其发展为前列腺癌。两个特定的目标被提出来解决两个重要的问题：1)PIN的启动和进展是否完全依赖于雄激素，以及雄激素消融能否阻止PIN向前列腺癌的恶性进展？2)非典型细胞在PIN病变中的细胞和分子特性是什么，雄激素信号的异常激活如何诱导PIN的启动和癌的进展？

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?