The role of CAR and its application in bladder cancer

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DESCRIPTION (provided by applicant): With over 50,000 new cases and 10,000 deaths expected this year in the U.S, bladder cancer is a significant health concern. Variable morphology, natural history, and prognosis demonstrate that transitional cell carcinoma (TCC) of the bladder is not a single disease, but occurs in three distinct forms, each possessing characteristic features (i.e., low grade papillary, noninvasive; carcinoma in situ; high grade, invasive). Recent studies have begun to elucidate the underlying genetic determinants of the morphologic and biologic characteristics of these different presentations of bladder cancer. Molecular and genetic alterations that precede morphologic changes, and which are responsible for tumorigenesis and progression of TCC. Understanding these genetic changes should eventually lead to improved diagnosis and gene therapy for TCC. Identification of a coxsackie and adenovirus receptor (CAR), a high receptor for adenovirus type 5, was recently reported. The heterogeneous expression of CAR is detected in several TCC and prostate cancer cell lines. This expression resulted from the downregulation of CAR gene transcription. By increasing their CAR levels, resistant cells could become highly sensitive to adenoviral infection. Therefore, CAR not only is a surrogate marker to monitor the outcome of gene therapy, but also facilitate the efficiency of gene therapy. The Down-regulation of CAR is often seen in TCC lesions but not in adjacent normal tissue, which suggests that CAR may play a pathophysiologic role in the progression of TCC. Also, CAR is associated with a tight junction protein in differentiated polarized cell. Moreover, increased CAR gene expression can inhibit the in vitro and in vivo growth of tumor cells. On the other hand, decreasing CAR expression (using antisense vector) in several TCC cell lines can facilitate the in vitro and in vivo growth rate. These data indicate that CAR is a tumor inhibitor in TCC cells. To further elucidate the underlying mechanism of CAR in TCC cells, preliminary data indicated that (1) CAR is a typical cell adhesion molecule; (2) CAR is associated with tight junction complex; (3) adhesion activity of CAR parallels its growth inhibitory function; (4) the intracellular domain of CAR is critical for inducing its growth inhibitory signal in TCC cells; (5) CAR is able to inhibit cyclooxygenase 2 (COX-2) expression. Based on these results, we hypothesize that CAR can inhibit cell growth by reestablishing intercellular interactions of TCC, and the mechanism of CAR action is to inhibit COX-2 expression in TCC. Since the biology of CAR and COX-2 is largely unknown, we plan to (1) establish a reciprocal relationship between CAR and COX-2 from TCC specimens of different grades and stages; (2) unveil downstream pathway(s) elicited by CAR that activates its tumor inhibition and to determine any other ligand(s) capable of activating CAR signaling; (3) determine the biologic significance of the suppression of COX-2 by CAR; (4) increase therapeutic efficacy of TCC gene therapy by enhancing its endogenous CAR expression. The outcome of this study should help us understand the biologic role of CAR in the progression of TCC and develop a new strategy for TCC therapy.