Applications of Exosomes in Diagnosing Muscle Invasive Bladder Cancer

Abstract

Muscle Invasive Bladder Cancer (MIBC) is a subset of bladder cancer with a significant risk for metastases and death. It accounts for nearly 25% of bladder cancer diagnoses. A diagnostic work-up for MIBC is inclusive of urologic evaluation, radiographic imaging with a CT scan, urinalysis, and cystoscopy. These evaluations, especially cystoscopy, are invasive and carry the risk of secondary health concerns. Non-invasive diagnostics such as urine cytology are an attractive alternative currently being investigated to mitigate the requirement for cystoscopy. A pitfall in urine cytology is the lack of available options with high reliability, specificity, and sensitivity to malignant bladder cells. Exosomes are a novel biomarker source which could resolve some of the concerns with urine cytology, due to the high specificity as the surrogates of tumor cells. This review serves to define muscle invasive bladder cancer, current urine cytology methods, the role of exosomes in MIBC, and exosomes application as a diagnostic tool in MIBC. Urinary exosomes as the specific populations of extracellular vesicles could provide additional biomarkers with specificity and sensitivity to bladder malignancies, which are a consistent source of cellular information to direct clinicians for developing treatment strategies. Given its strong presence and differentiation ability between normal and cancerous cells, exosome-based urine cytology is highly promising in providing a perspective of a patient's bladder cancer.

Keywords: biomarkers; bladder cancer diagnosis; bladder cancer screening; exosomes; muscle invasive bladder cancer.

Figure 1

(A) The bladder cancer dual pathway involves the presence of papillary or non-papillary lesions. papillary lesions harbor mutations in FGFR3, TERT, PIP3, and deletion of CDKN2A on Chromosome 9. Papillary lesions typically present as NMIBC. Non-papillary lesions include mutation of TERT, PIP3, FGFR3, p53, Rb1, and deletion of CDKN2A on chromosome 9. Non-papillary lesions typically describe MIBC. (B) The bladder consists of four layers: the epithelium, submucosa, detrusor muscle, and parietal peritoneum. Staging for bladder cancer is depicted in this figure. Tumors are classified based on the TNM grading system where T describes the primary tumor in terms of its size and tissue penetration. N characterizes the involvement, or lack thereof, lymph nodes. M describes the presence of absence of metastasis. MIBC is characterized by being T2 and can present with or without nodal or metastatic involvement.

Figure 2

Exosomes are involved in cancer cell development, proliferation, and survival. (A) Through autocrine communication, exosomes communicate to the cells they are released from to promote a suitable microenvironment for tumors and contribute to the activation of pro-tumor mutations within their host cell. (B) Paracrine communication allows exosomes to communicate to nearby cells. They can modify the signaling pathways leading to changes in gene expression of surrounding cells. (C) Exosome’s role in the epithelial to mesenchymal transition (EMT). (D) In hypoxic conditions exosomes can promote the growth of new blood vessels, often called angiogenesis. Through this process, nutrients can be sent to malformed cells to support their growth and proliferation into cancer cells. (E) Through exosome regulation of cellular communication, changing the histology of the tissue could create a more suitable tumor microenvironment. This process supports more malignant forms of cancer. The cellular communication of exosomes to distant sites allows them to prepare distant organs for later infiltration of tum or cells.