Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer.
OBJECTIVE
To evaluate the expression of the coxsackie and adenovirus receptor (CAR) and alpha(v) integrins in clinical specimens of bladder cancer to determine the susceptibility to adenoviral gene therapy. Efficient adenovirus-based gene therapy requires binding of the virus to CAR and involves the alpha(v) integrins. Studies on bladder cancer cell lines have shown that low adenoviral transduction rates were associated with low-level expression of CAR. Integrin alpha(v) expression increases in various tumors suggest its importance in differentiation, proliferation, and migration. CAR is structurally a member of the Ig-type superfamily of cell-cell adhesion molecules, suggesting that its expression may also be related to the state of tumor differentiation.


METHODS
We performed immunohistochemistry for CAR and integrin alpha(v) expression in bladder cancer specimens in 50 paraffin-embedded tumor-normal pairs and confirmed the results by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of 11 separate bladder tumors and 4 separate normal bladder controls.


RESULTS
Immunochemistry demonstrated a stage and grade-dependent decrease in CAR expression (90.0%, 83.3%, and 31.3% of normal urothelium and superficial and invasive transitional cell carcinoma [TCC] and 83.3% and 39.5% of low and high-grade TCC, respectively). Furthermore, we found a stage and grade-dependent increase in alpha(v) integrin expression (13.3%, 46.0%, and 56.3% of normal urothelium, superficial TCC, and invasive TCC and 25% and 52.6% of low and high-grade TCC, respectively). Quantitative RT-PCR analysis confirmed a downregulation at the CAR gene expression level.


CONCLUSIONS
This down-regulation may have a major impact on developing adenoviral-based gene therapy modalities. In addition, we propose that loss of CAR expression decreases rigid cell adhesion, possibly increasing the migratory potential. Loss of CAR expression correlates with the invasive phenotype in our analysis of bladder cancer. Simultaneously, the finding of increased alpha(v) expression in invasive cancer suggests a pathogenesis that involves heterophilic adhesion and migration of these cells on various extracellular ligands.
D000256:Adenoviridae / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D039564:Integrin alphaV; D011991:Receptors, Virus