845. The Loss Expression of Coxsackie and Adenovirus Receptor Enhances the Feature of Aggressive Bladder Cancer

• Published in: Molecular therapy Vol. 13; no. S1; p. S326
• Main Authors: Matsumoto, Kazumasa, Shariat, Sharokh F., Irie, Akira, Fujita, Tetsuo, Okusa, Hiroshi, Satoh, Takefumi, Iwamura, Masatsugu, Baba, Shiro, Lerner, Seth P.
• Format: Journal Article
• Language: English
• Published: Milwaukee Elsevier Limited 01.05.2006
• Subjects: Bladder cancer
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2006.08.931

Objectives. Adenovirus is a useful vector for cancer gene delivery because of its high gene transfer efficacy, high titer production, and safety. The initial binding of adenoviruses except for serotype B to cell surface is mediated via a specific 46 kDa coxsackie and adenovirus receptor (CAR). In addition, recent evidence suggested that CD46, a complement inhibitory protein, plays a role as a serotype B Ad receptor. Low levels of CAR are associated with decreased efficiency of adenovirus-mediated gene transduction of bladder cancer. In present study, we evaluated the expression of CAR and CD46 in urologic cancer cell lines, and then examined whether CAR expression is associated with bladder cancer characteristics and clinical outcomes.Methods. CAR and CD46 expression in urologic cancer cell lines were determined by flow cytometry. Immunohistochemical staining for CAR was carried out on surgical specimens from 62 patients who underwent radical cystectomy. Immunoreactivity was categorized on a 0-3+ semiquantitation system for both intensities of staining and the percentage of positive cells (labeling frequency %). We also stained 30 tumor section specimens from normal sections for microvessel density, E-cadherin, pRB, p16, p21, p53, cyclooxygenase-2, and transforming growth factor-beta1 and its receptors type I and II.Results. Low expression of CAR and high expression of CD46 were determined in urologic cancer cell lines. In immunohistochemical staining, CAR expression was lost in 17/62 (27%) tumors. Loss of CAR expression was associated with metastases to regional lymph nodes (p=0.049), muscle-invasive disease (p=0.025), high grade disease (p=0.038), altered p53 status (p=0.041), and loss of E-cadherin expression (p=0.042). With a median follow-up of 60 months, loss of CAR expression was associated with decreased bladder cancer-specific survival (p=0.029) but not disease progression. When adjusted for the effects of clinicopathologic findings, only lymph node metastasis was associated with bladder cancer progression and mortality.Conclusions. Loss of CAR expression is associated with established markers of biologically aggressive bladder cancer. The CAR dependence of the adenovirus vector may result in sequestration of recombinant virions by biologically less aggressive yet high-CAR- expressing bladder cancer cells, whereas the targeted aggressive bladder cancer cells, low in CAR, will be poorly transduced. The association of CAR with E-cadherin and p53 suggests a potential role for CAR in the regulation of urothelium integrity and cell cycle.