Human urinary bladder carcinomas express adenovirus attachment and internalization receptors

Loskog, Angelica; Hedlund, T.; Wester, Kenneth; Torre, Manuel de la; Philipson, Lennart; Malmström, P-U.; Tötterman, Thomas H.

doi:10.1038/sj.gt.3301689

Cited by 17 publications

(3 citation statements)

References 17 publications

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“…Our observation that all the tumour biopsies we have tested can be successfully transduced by adenovirus is in keeping with data recently published by Loskog et al,21 showing that all 27 bladder tumour specimens examined showed detectable levels of expression of hCAR by immunohistochemistry, with hCAR expression being higher in superficial than in muscle-invasive tumours. Our results showing that the efficiency of transduction of freshly biopsied human TCC specimens is at least as high as in intact urothelium, despite a much lower concentration of virus, suggests a degree of tumour selectivity, possibly because of disruption of a physical barrier in tumours.…”

Section: Discussionsupporting

confidence: 76%

Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo

et al. 2003

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Existing local therapies for superficial transitional cell carcinoma (TCC) of the bladder have limited success in preventing progression to life-threatening, muscle-invasive disease, and novel therapies are needed. Recent studies have raised doubts concerning the feasibility of adenovirusmediated gene therapy for bladder cancer. We have therefore investigated adenoviral transduction of normal and malignant human urothelial cells, both as primary cultures and in intact epithelium. All 15 primary normal human urothelial cell lines tested were transduced in vitro by Adv-cmv-b-gal at high efficiency, and better than most human TCC cell lines. Eight primary human TCC explants were also successfully transduced. In contrast, in intact normal urothelium, transduction efficiency was lower, and occurred only in superficial epithelial layers. Expression of the hCAR adenovirus receptor, however, occurred throughout the full thickness of urothelium. Transduction of human TCC biopsy specimens was at least as efficient as intact normal urothelium. We demonstrate for the first time that adenoviral transduction of both normal and malignant human urothelial cells is feasible. A physical barrier, rather than hCAR status, may be the main determinant of transduction of intact epithelium. Clinical trials of adenovirus-mediated gene therapy for superficial bladder cancer are warranted.

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Section: Discussionsupporting

confidence: 76%

Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo

et al. 2003

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“…The T24 cell line has, in some studies, been reported to be coxsackie/ adenovirus receptor (CAR) negative and, therefore, a poor target for viral replication (32). However, Loskog et al have previously reported that the T24 cell line cultured in our laboratory is CAR positive by reverse transcription-PCR (33) and Western blot. Fig.…”

Section: Resultsmentioning

confidence: 96%

A Novel Chromogranin-A Promoter-Driven Oncolytic Adenovirus for Midgut Carcinoid Therapy

Leja

Dzojic

Gustafson³

et al. 2007

Clinical Cancer Research

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Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids.We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene. Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases. Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types.Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes. Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.

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“…Adenoviral vectors have several features that make them desirable as gene delivery vehicles, such as their capacity to transduce both resting and proliferating cells and their transient gene expression, which is desirable for immunotherapy. We have shown that the virus attachment receptor Coxsackie-adenoviral receptor (CAR) is abundantly expressed in human tumour biopsies (Loskog et al 2002b). There are, however, two major obstacles that need to be circumvented in order for efficient viral transduction of the bladder wall to occur.…”

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confidence: 99%

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

et al. 2005

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SummaryBladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting.The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate.Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

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Human urinary bladder carcinomas express adenovirus attachment and internalization receptors

Cited by 17 publications

References 17 publications

Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo

Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo

A Novel Chromogranin-A Promoter-Driven Oncolytic Adenovirus for Midgut Carcinoid Therapy

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

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