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.
This high recurrence rate in non-muscle invasive bladder cancer (BC) and high morbidity and mortality in muscle invasive BC make it one of the most burdensome cancers to manage and treat. Thus, 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. Our studies found that BC exosomes mediate cell-cell communication between urothelial cells and cells in the surrounding microenvironment, providing a novel mechanism to explain bladder cancer field effects, tumor recurrence, and disease progression. In addition, the non-invasive nature of urine sample collection, the evolving biological significance of exosomes, and quantitative analysis of biomolecular isolation from BC patients' urinary exosomes may allow an easy and rapid screening for BC genetic markers and offer new diagnostic and prognostic information.
|Silvers, Christopher R; Miyamoto, Hiroshi; Messing, Edward M et al. (2017) Characterization of urinary extracellular vesicle proteins in muscle-invasive bladder cancer. Oncotarget 8:91199-91208|
|Silvers, Christopher R; Liu, Yu-Ru; Wu, Chia-Hao et al. (2016) Identification of extracellular vesicle-borne periostin as a feature of muscle-invasive bladder cancer. Oncotarget 7:23335-45|