Smooth muscle invasion selects for aggressive prostate cancer

项目总结/摘要 前列腺癌是美国男性中最常见的非皮肤癌，其特征在于大量的 过度诊断的程度，因此是发病率的重要来源和不必要成本的驱动因素。 因此，有一个显着的需要，以确定前列腺癌患者谁需要积极的治疗相比， 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性肿瘤。 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内渗和外渗。此外，癌症- 人前列腺的倾向性外周区由纤维肌性基质组成，并由 平滑肌囊虽然大多数癌症的当前范例是局部侵袭不能预测癌症的发生， 前列腺癌是一种恶性肿瘤，它是一种恶性肿瘤。侵袭性前列腺癌细胞直接 在称为囊外延伸的过程中，观察到成簇延伸通过平滑肌囊 (ECE)从而逃离器官限制。ECE的存在定义了病理学中的pT 3a类别。 前列腺腺癌的分期，并与生化复发的风险增加有关， 转移和癌症特异性死亡率。尽管ECE需要平滑肌浸润，但血管内渗， 和外渗到远处的部位，没有从惰性到侵略性，肌肉侵入性的转变的标志物 前列腺癌因此，这项工作集中在了解调控ECE的分子事件 以阻止转移过程中的这一关键步骤。核心假设是，通过 平滑肌囊需要独特分子特性来预测侵袭性癌症。如果正确的话， 该概念将通过提供惰性与惰性的新分子鉴别器来改变当前的护理标准 侵袭性疾病侵袭性疾病转变的客观测量将为治疗决策提供信息， 有助于指导针对疾病侵袭程度的相应治疗水平。

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.