How Cancer Cells Invade Bladder Epithelium and Form Tumors: The Mouse Bladder Tumor Model as a Model of Tumor Recurrence in Patients.

Andreja Erman,Urška Dragin Jerman,Rok Romih,Peter Veranič,Maja Čemažar,Mojca Pavlin,Urška Kamenšek

doi:10.3390/ijms22126328

Abstract

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3β1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients.

Highlights

Urinary bladder cancer is one of the most common malignancies worldwide and is categorized as non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC)
We focused on junctional proteins, such as N-cadherin, β-catenin, desmoplakins 1 and 2, and α-integrin, and used various light and electron microscopy techniques to identify the type of cell–cell contacts
Experimental and clinical data show that bladder tumor recurrence could be due to either intraepithelial expansion of cancer cells from the existing tumor or shedding of cancer cells from the tumor cell mass and their reattachment on traumatized urothelium caused by resection of the tumor [5,32,33]

Summary

Introduction

Urinary bladder cancer is one of the most common malignancies worldwide and is categorized as non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). Most (75–85%) bladder cancer incidences are non-muscle-invasive and the remaining are either muscle-invasive or metastatic diseases. Despite the transurethral resection of bladder tumor (TURBT) as a standard treatment of NMIC, up to 50% of patients develop tumor recurrence in 5 years and 88% of patients in 15 years [1,2,3]. Several proposals have been made to explain the high recurrence of bladder tumors. One of them suggests that urothelial cancer cells that have been released from the tumor cell mass during TURBT could subsequently reattach to the traumatized bladder epithelium [5,6]. Recognizing the fate of disseminated cancer cells in the bladder lumen and knowing the very first events of urothelial cancer cell implantation is of great importance to understand the mechanisms of recurrence

Methods

Results

Conclusion