Loss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer

doi:10.1016/j.urology.2005.02.033

Urology

Volume 66, Issue 2, August 2005, Pages 441-446

https://doi.org/10.1016/j.urology.2005.02.033 Get rights and content

Abstract

Objectives

To examine whether loss of coxsackie and adenovirus receptor (CAR) expression is associated with bladder cancer characteristics and clinical outcomes and with expression of p53 and E-cadherin. Low levels of CAR are associated with decreased efficiency of adenovirus-mediated gene transduction of bladder transitional cell carcinoma.

Methods

Immunohistochemical staining for CAR and p53 was carried out on tissue microarrays from 62 patients who had undergone radical cystectomy. We also examined 30 specimens for E-cadherin expression.

Results

CAR expression was lost in 17 (27%) of 62 tumors. Loss of CAR expression was associated with metastases to regional lymph nodes (P = 0.049), muscle-invasive disease (P = 0.025), grade 3 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 standard pathologic features, only lymph node metastasis was associated with bladder transitional cell carcinoma progression and mortality.

Conclusions

Loss of CAR expression is associated with established markers of biologically aggressive bladder transitional cell carcinoma. The association of CAR with E-cadherin and p53 suggests a potential role for CAR in the regulation of urothelium integrity and the cell cycle.

Section snippets

Patient Population

We studied 62 patients with TCC of the urinary bladder who had undergone radical cystectomy with pelvic and iliac lymphadenectomy and for whom we had adequate archival material. Histopathologic characteristics were confirmed by blinded review of the original pathology slides. The 1997 TNM classification was used for pathologic staging, and the World Health Organization classification was used for pathologic grading. No patient was treated preoperatively with either radiotherapy or systemic

Association of CAR Expression with Clinicopathologic Characteristics and Molecular Markers

A representative result of the immunohistochemistry for CAR in cancerous bladder tissues is shown in Figure 1. The positive staining bladder cancer epithelium had distinct circumferential CAR immunoreactivity of high intensity (Fig. 1A). Intact CAR immunostaining was noted in 9 (15%) of 62 patients. Complete loss of CAR staining was found in 17 (27%) of 62 tumors (Fig. 1B). In most tumors (36 of 62, 58%), the specimens showed a focal pattern of heterogeneity. The clinicopathologic

Comment

Our findings, consistent with the observation of Sachs et al.,⁸ demonstrated that loss of CAR expression was associated with features of biologically aggressive bladder TCC, such as grade 3 and muscle-invasive disease. In addition, we found that CAR expression was altered in patients harboring metastasis to regional lymph nodes. Although the association between CAR expression and pathologic characteristics is important, an association with more significant endpoints such as bladder cancer

Conclusions

Loss of CAR expression is associated with established markers of biologically aggressive bladder TCC such as lymph node metastases and pathologic stage and grade, but not disease progression or survival. The CAR dependence of the adenovirus vector may result in sequestration of recombinant virions by biologically less aggressive, yet high CAR-expressing, TCC cells, with the targeted aggressive TCC cells, low in CAR, poorly transduced. The association of CAR with the cell adhesion marker

Acknowledgment

To Onyx Pharmaceuticals for the use of their antibody, CAR72.

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: This study was supported by grants from the Frost Foundation, Inc., Austrian Program for Advanced Research and Technology (SFS), and University of California, San Francisco, Comprehensive Cancer Center Specialized Program in Research Excellence (SPORE) in Prostate Cancer, grant P50CA89520 (K.A.R.).

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Basic scienceLoss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Patient Population

Association of CAR Expression with Clinicopathologic Characteristics and Molecular Markers

Comment

Conclusions

Acknowledgment

Urology

Mol Ther

Cell

Urology

Urology

J Urol

Int J Radiat Oncol Biol Phys

Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5

Science

The presence of human coxsackievirus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures

Hum Gene Ther

Differential susceptibility of primary and established human glioma cells to adenovirus infectiontargeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer

Cancer Res

Loss of adenoviral receptor expression in human bladder cancer cellsa potential impact on the efficacy of gene therapy

Cancer Res

The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancera functional analysis of CAR protein structure

Cancer Res

Basic science
Loss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer