Exosomes: A novel mechanism for bladder cancer tumorigenesis and progression

描述（由申请人提供）：膀胱癌（BC）是美国第五大最常见的恶性肿瘤。大多数BC患者患有非肌肉侵袭性（NMI）疾病，这些肿瘤经常在经尿道切除初始肿瘤后复发。大约25-30%的BC患者有肌肉侵袭性疾病（MIBC）。不幸的是，50%的心肌梗死患者会发展为转移性疾病，5年生存率为10%。NMI BC的高复发率、高发病率和高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，这将导致开发特定阶段的治疗靶点，以防止肿瘤复发和进展。

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.