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Int. J. Mol. Sci. 2018, 19(9), 2694; https://doi.org/10.3390/ijms19092694

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

1
Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Korea
2
Institute of Genome Research, Vietnam Academy of Science and Technology, Hanoi 122121, Viet Nam
3
Department of Urology, Chonnam National University Medical School, Gwangju 61469, Korea
4
Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Korea
5
Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju 61469, Korea
6
Genitourinary Cancer Branch, Research Institute of National Cancer Center, Goyang 10408, Gyeonggi-do, Korea
7
Institute of Molecular Life Sciences, University of Zurich, Zurich 8057, Switzerland
*
Author to whom correspondence should be addressed.
Received: 20 August 2018 / Revised: 30 August 2018 / Accepted: 6 September 2018 / Published: 10 September 2018
(This article belongs to the Special Issue Gene Therapy)
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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. View Full-Text
Keywords: CD46; CAR; adenovirus; gene therapy; bladder cancer CD46; CAR; adenovirus; gene therapy; bladder cancer
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Do, M.-H.; To, P.K.; Cho, Y.-S.; Kwon, S.-Y.; Hwang, E.C.; Choi, C.; Cho, S.-H.; Lee, S.-J.; Hemmi, S.; Jung, C. Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer. Int. J. Mol. Sci. 2018, 19, 2694.

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