Exosomes: A novel mechanism for bladder cancer tumorigenesis and progression

描述(申请人提供)：膀胱癌(BC)是美国第五种最常见的恶性肿瘤。大多数BC患者有非肌肉侵袭性(NMI)疾病，这些肿瘤在最初的肿瘤经尿道电切后经常复发。大约25%-30%的BC患者患有肌肉侵袭性疾病(MIBC)。不幸的是，50%的MI BC患者将发展为转移性疾病，5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最难管理和治疗的癌症之一。因此，很有必要了解这些肿瘤的生物学基础，从而开发阶段特异性的治疗靶点，以防止肿瘤的复发和进展。 小的细胞外膜结合的囊泡称为外体，可以从被邻近细胞占据的多种类型的细胞中分泌出来，从而影响它们的行为。越来越多的证据支持这一理论，即癌症外切体在癌症发生和发展的许多步骤中起着至关重要的作用。初步研究表明，BC外切体可促进BC细胞的迁移、侵袭和血管生成。已鉴定出多种BC外切体蛋白，其中EDIL-3在BC外切体中与正常对照相比过度表达，并且敲除EDIL-3可减少癌症外切体介导的BC细胞迁移和血管生成。机制研究表明，EDIL-3可以激活FAK和EGFR等跨膜蛋白，从而诱导信号级联影响细胞的增殖和迁移。基于初步研究，我们假设BC来源的外切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，BC患者的尿外切体蛋白图谱可以作为疾病的生物标志物。 提出了四个目标来研究外显体在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：研究8种肿瘤相关胞外蛋白在肿瘤进展中的作用。目的：探讨癌相关蛋白在BC患者尿外切体中的表达及功能。目的4：研究肿瘤外切体在体内促进肿瘤进展的能力。我们的长期目标是了解癌症外切体的生物学功能，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.