Exosomes: A novel mechanism for bladder cancer tumorigenesis and progression

描述（由申请人提供）：膀胱癌（BC）是美国第五大最常诊断的恶性肿瘤。大多数BC患者患有非肌肉浸润性（NMI）疾病，这些肿瘤在经尿道切除初始肿瘤后经常复发。大约25-30%的BC患者患有肌肉浸润性疾病（MIBC）。不幸的是，50%的MI BC患者将发展为转移性疾病，五年生存率为10%。NMI BC的高复发率以及MI BC的高发病率和死亡率使其成为管理和治疗最繁重的癌症之一。因此，非常需要了解这些肿瘤的潜在生物学，这将导致开发阶段特异性治疗靶点以防止肿瘤复发和进展。 小的细胞外膜结合囊泡，称为外泌体，可以从许多类型的细胞分泌，被邻近细胞摄取，从而影响它们的行为。越来越多的证据支持癌症外泌体在癌症发展和进展的许多步骤中发挥重要作用的理论。初步研究表明，BC外泌体促进BC细胞迁移、侵袭和血管生成。鉴定了几种BC外泌体蛋白，其中发现EDIL-3与正常对照相比在BC外泌体中过表达，并且敲低EDIL 3减少了癌症外泌体介导的BC细胞迁移和血管生成。机制研究表明，EDIL-3可激活跨膜激酶如FAK和EGFR，从而诱导信号级联影响细胞增殖和迁移。基于初步研究，我们假设BC衍生的外泌体通过旁分泌方式将癌症相关蛋白转移到受体细胞，从而促进肿瘤进展。此外，来自BC患者的尿外泌体蛋白质谱可以用作疾病生物标志物。 提出了四个目的来研究外泌体在BC生物学中的作用。目的1：阐明EDIL-3促进膀胱进展的潜在机制。目的2：研究8种癌相关外泌体蛋白在肿瘤发生发展中的作用。目的3：探讨膀胱癌患者尿液exosomes中癌相关蛋白的表达及功能。目的4：研究癌外泌体在体内促进癌进展的能力。我们的长期目标是了解癌症外泌体的生物学功能，并揭示可能的新治疗靶点。

DESCRIPTION (provided by applicant): Bladder cancer (BC) is the fifth most commonly diagnosed malignancy in the United States. The majority of BC patients have non-muscle invasive (NMI) disease, and these tumors frequently recur after transurethral resection of initial tumors. Approximately 25-30% of BC patients have muscle invasive disease (MIBC). Unfortunately, 50% of MI BC patients will develop metastatic disease with 10% five year survival rate. This high recurrence rate in NMI BC, and high morbidity and mortality in MI BC make it one of the most burdensome cancers to manage and treat. Therefore, there is a great need for understanding the underlying biology of these tumors which would lead to the development of stage specific therapeutic targets to prevent tumor recurrence and progression. Small extracellular membrane bound vesicles, termed exosomes, can be secreted from numerous types of cells taken up by neighboring cells, consequently affecting their behaviors. There is increasing evidence supporting the theory that cancer exosomes play vital roles in many steps of cancer development and progression. Preliminary studies showed that BC exosomes promote BC cell migration, invasion and angiogenesis. Several BC exosome proteins were identified, among which EDIL-3 is found to be over-expressed in BC exosomes as compared to normal controls, and knocking down EDIL3 reduced cancer exosome-mediated BC cell migration and angiogenesis. Mechanistic studies indicated that EDIL-3 can activate the transmembrane kinases such as FAK and EGFR, consequently inducing a signal cascade to influence cell proliferation and migration. Based on preliminary studies, we hypothesize that BC-derived exosomes, via the paracrine manner that transfers cancer-associated proteins to recipient cells, consequently promote tumor progression. Moreover, urinary exosome protein profiles from BC patients can serve as disease biomarkers. Four Aims are proposed to study exosome roles in BC biology. Aim 1: To delineate underlying mechanisms by which EDIL-3 promotes bladder progression. Aim 2: To study the roles of 8 cancer-associated exosomal proteins on tumor progression. Aim 3: To determine the expression and function of those cancer-associated proteins in urinary exosomes of BC patients. Aim 4: To study cancer exosome ability to promote cancer progression in vivo. Our long-term goal is to understand the biological functions of cancer exosomes and to reveal possible novel treatment targets.