Smooth muscle invasion selects for aggressive prostate cancer

项目摘要/摘要 前列腺癌是美国男性最常见的非皮肤癌，其特点是 这是过度诊断的严重程度，因此是发病率的重要来源和不必要成本的驱动因素。 因此，有必要识别需要积极治疗的前列腺癌患者进行比较。 给那些根本不需要治疗的人。这些肿瘤的癌症特异性死亡率可归因于转移。 疾病。前列腺癌必须在转移的多个步骤中与平滑肌相互作用 过程，包括血流和组织之间的渗入和渗出。另外，癌症-- 人前列腺的俯卧周边区由纤维肌肉间质组成，并由 平滑肌肉胶囊。虽然目前对大多数癌症的范例是局部侵袭不能预测 侵袭性疾病，前列腺癌不是这样。侵袭性前列腺癌细胞直接 观察到在称为囊外延伸的过程中，一簇簇地延伸过平滑肌囊 (Ece)，从而逃脱器官限制。ECEs的存在定义了病理中的pT3a类别 前列腺癌的分期与生化复发风险的增加有关 转移和癌症特有的死亡率。尽管ECEs需要平滑肌侵入，但血管内注射， 以及渗出到远处的部位，没有从惰性到侵袭性、肌肉侵袭性转变的标志 前列腺癌。因此，这项工作集中在了解调节欧洲经委会的分子事件 以防止转移过程中的这一关键步骤。中心假设是通过 平滑肌胶囊需要独特的分子特性来预测侵袭性癌症。如果是正确的， 该概念将改变目前的护理标准，通过提供新的分子鉴别器来区分懒惰和 侵袭性疾病。攻击性疾病转变的客观措施将为治疗决策和 帮助指导对疾病攻击性程度的适当治疗。

PROJECT SUMMARY/ABSTRACT The most common non-cutaneous cancer in American men, prostate cancer is characterized by a substantial degree of overdiagnosis and is consequently a significant source of morbidity and driver of unnecessary cost. There is therefore a significant need to identify prostate cancer patients who need aggressive therapy compared to those who need no treatment at all. The cancer-specific mortality of these tumors is attributable to metastatic disease. Adenocarcinoma of the prostate must interact with smooth muscle at multiple steps of the metastatic process, including intravasation and extravasation between the bloodstream and tissue. In addition, the cancer- prone peripheral zone of the human prostate gland is composed of a fibromuscular stroma and bounded by a smooth muscle capsule. While the current paradigm for most cancers is that local invasion is not predictive of aggressive disease, this is not the case with prostate cancer. Aggressive prostate cancer cells are directly observed as extending past the smooth muscle capsule in clusters, in a process called extracapsular extension (ECE), thereby escaping organ confinement. The presence of ECE defines the pT3a category in the pathologic staging of prostatic adenocarcinoma and is associated with an increased risk of biochemical recurrence, distant metastases and cancer-specific mortality. Although smooth muscle invasion is required for ECE, intravasation, and extravasation to distant sites, there are no markers of the switch from indolent to aggressive, muscle-invasive prostate cancer. This work is therefore concentrated on understanding the molecular events that regulate ECE to prevent this critical step in the metastatic process. The central hypothesis is that invasion through the smooth muscle capsule requires unique molecular properties that predict aggressive cancer. If correct, the concept will change current standard of care by providing new molecular discriminators of indolent versus aggressive disease. Objective measures of the aggressive disease transition will inform treatment decisions and help to direct the appropriate level of treatment for the degree of disease aggression.