Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer.

Manh-Hung Do,Chan Choi,Chaeyong Jung,Se-Young Kwon,Eu Hwang,Silvio Hemmi,Sang-Hee Cho,Sang-Jin Lee,Phuong To,Young-Suk Cho

doi:10.3390/ijms19092694

Abstract

CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

Highlights

According to estimates by the American Cancer Society, approximately 81,190 people will be diagnosed in 2018 with bladder cancer, and approximately 17,240 people will be died from this disease in the United States [1]
While the expression of both coxsackie-adenoviral receptor (CAR) and CD46 was very low in normal urothelium, tumor cells derived from the bladder epithelium showed mixed results
CAR expression was observed in 37 bladder tumors out of 59, whereas CD46 was observed in 29 bladder tumors

Summary

Introduction

According to estimates by the American Cancer Society, approximately 81,190 people will be diagnosed in 2018 with bladder cancer, and approximately 17,240 people will be died from this disease in the United States [1]. Bladder cancer is the most frequent cancer found in the urinary system, and the fourth most common cancer in men. It is more common in males, bladder cancer is prevalent in females. Several strategies have been used to treat bladder cancer such as surgical resection, chemotherapy, immunotherapy, or irradiation. The poor survival rate and high frequency of recurrence require alternative and more efficient strategies [2,3,4]. Over the last few decades, viral cancer gene therapy has been suggested as an effective alternative therapy for controlling cancer, in particular for the treatment of bladder cancers [3,5]

Methods

Results

Discussion

Conclusion