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Human urinary bladder carcinomas express adenovirus attachment and internalization receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology. (Gen och immunoterapi gruppen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Experimentell urologi)
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2002 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 9, no 9, 547-553 p.Article in journal (Refereed) Published
Abstract [en]

The use of adenoviral vectors as potent gene delivery systems requires expression of the Coxsackievirus/adenovirus receptor (CVADR) on the target cell surface. This receptor is important for virus attachment to the cell surface. For effective internalization of the vector into the target cell the integrins alpha(v)beta(3) and/or alpha(v)beta(5) are needed. Since there have been reports of loss of CVADR in bladder cancer cell lines, we wanted to investigate the expression of this receptor in bladder carcinoma biopsies. Surgical biopsies, as well as five human bladder cancer cell lines, were analyzed for expression of CVADR, the integrins alpha(v)beta(3) and alpha(v)beta(5) and MHC class I. Further, we studied the ability to transduce these cell lines using adenoviral vectors. Immunohistochemistry revealed that all biopsies (27/27) were positive for CVADR. Some variation in expression was evident, and superficially growing tumors stained more strongly than invasive ones. Most human tumors expressed the integrin alpha(v)beta(5) (14/24), whereas integrin alpha(v)beta(3) was less frequently seen (3/20). The established cell lines were efficiently transduced with adenoviral vectors, and transduction could be reduced with anti-CVADR antibodies. The abundance of appropriate viral receptors on tumor biopsy cells is a further argument for using adenoviral vectors in gene therapy of bladder cancer.

Place, publisher, year, edition, pages
2002. Vol. 9, no 9, 547-553 p.
Keyword [en]
adenovirus, CVADR, CAR, integrins, bladder cancer
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-89986DOI: 10.1038/sj.gt.3301689PubMedID: 11973630OAI: oai:DiVA.org:uu-89986DiVA: diva2:161977
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
Open this publication in new window or tab >>Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis comprises studies on murine and human models of bladder carcinoma with the aim to develop novel immunogene therapies. On the basis of the results presented in this thesis, a clinical trial is underway.

The potential of activating the immune system to combat cancer has long intrigued immunologists. Research has now been intensified and clinically effective treatments are beginning to materialize. We evaluated the induction of anti-tumor responses by inserting immunomodulating genes into tumor cells with adenovectors. Human biopsies and cell lines were positive for adenovirus attachment receptors, and cell lines were easily transduced. CD40L modified cells efficiently induced maturation of dendritic cell (DC). Phenotypical changes of AdCD40L transduced cells, such as increased apoptotic rate, upregulated MHC-I, Fas and TNFR may further strengthen the anti-tumor response.

CD40L modified murine bladder cancer cells activated systemic immunity upon vaccination and in situ injections of AdCD40L inhibited tumor progression. Cytotoxic assays revealed the presence of cytotoxic T cells (CTLs) in vaccinated mice. Many tumors have developed ways to evade the immune system. Bladder carcinoma is associated with immune escape mechanisms like IL10 production. We demonstrated that immunosuppression by IL10 inhibited CTL function and that IL10 suppression may be reverted by AdCD40L therapy.

In conclusion, AdCD40L therapy induces systemic immunity and inhibits tumor progression in murine models. The immunological mechanisms involve maturation of nearby DCs and CTL induction. AdCD40L therapy is effective despite immune escape mechanisms, e.g. IL10 secretion. The thesis argues for using AdCD40L immunogene therapy as a treatment of bladder carcinoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 52 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1180
Keyword
Oncology, Immunotherapy, Gene therapy, Immunogene therapy, CD40L, Bladder carcinoma, Onkologi
National Category
Cancer and Oncology
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-2637 (URN)91-554-5402-X (ISBN)
Public defence
2002-10-11, Rudbecksalen, Uppsala, 13:15
Opponent
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-09-15Bibliographically approved

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Loskog, AngelicaWester, KennethMalmström, Per-UnoTötterman, Thomas H.

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