Smooth muscle invasion selects for aggressive prostate cancer

平滑肌侵袭选择侵袭性前列腺癌

基本信息

批准号：
10207448
负责人：
Kendra Danice Marr
金额：
$ 3.8万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207448
关键词：
Address Aggressive behavior Algorithms American Biochemical Biological Assay Biophysics Bladder Blood Circulation CRISPR/Cas technology Cancer Patient Categories Cell surface Cells Cessation of life Clinical Complex Data Desmin Disease Distant Distant Metastasis Endometrial Event Exhibits Extracapsular Extravasation Gene Expression Gene Rearrangement Genes Head and Neck Cancer Histologic Human In Vitro Indolent Integrin Binding Integrin alpha6 Integrins Invaded Laminin Malignant Neoplasms Malignant neoplasm of prostate Measurable Measures Mediator of activation protein Metastatic to Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Mutation Organ Organoids Outcome PTEN gene Pathologic Pathological Staging Pathway interactions Patient Selection Patients Pattern Peripheral Phenotype Primary Neoplasm Process Prognosis Prognostic Marker Property Prostate Prostate Adenocarcinoma Prostatic Recurrence Risk Sampling Side Site Smooth Muscle Source Structure of capsule of prostate Testing Tissues Tumor Cell Migration Tumor-Derived Work aggressive therapy cancer type capsule clinical application clinically relevant cohesion cost curative treatments differential expression genetic signature improved in vivo insight mechanotransduction men metastatic process molecular pathology mortality mouse model neoplastic cell overtreatment patient derived xenograft model predictive signature prevent prognostic programs prostate cancer cell prostate cancer cell line receptor screening standard of care transcriptome sequencing tumor

项目摘要

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.

项目概要/摘要前列腺癌是美国男性中最常见的非皮肤癌，其特点是大量过度诊断的程度，因此是发病率的重要来源和不必要费用的驱动因素。因此，非常需要确定与癌症相比需要积极治疗的前列腺癌患者。对于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疾病。前列腺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—— 人类前列腺的外周区由纤维肌性基质组成，并以平滑肌囊。虽然大多数癌症的当前范例是局部侵袭并不能预测侵袭性疾病，但前列腺癌则不是这种情况。攻击性前列腺癌细胞直接观察到成簇延伸穿过平滑肌囊，这一过程称为囊外延伸（ECE），从而逃脱器官限制。 ECE 的存在定义了病理学中的 pT3a 类别前列腺腺癌的分期与生化复发、远处转移的风险增加相关转移和癌症特异性死亡率。虽然ECE需要平滑肌浸润，但内渗、和外渗到远处部位，没有从惰性转变为攻击性、肌肉侵入性的标志前列腺癌。因此，这项工作的重点是了解调节 ECE 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，入侵是通过平滑肌囊需要独特的分子特性来预测侵袭性癌症。如果正确的话，这一概念将通过提供新的惰性与惰性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根据疾病侵袭程度指导适当的治疗水平。