In Vitro and In Vivo Effects of CpG-Oligodeoxynucleotides (CpG-ODN) on Murine Transitional Cell Carcinoma and on the Native Murine Urinary Bladder Wall

Background: Intravesical BCG instillation is established and efficient in the prophylaxis of recurrent transitional cell carcinoma. A Th-1 biased immune response is postulated. Recent work has proven the efficacy of synthetic CpG-Oligodeoxynucleotides (ODN) as inducers and adjuvants for a strong Th1...

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Published in:Anticancer research 2009-06, Vol.29 (6), p.2067-2076
Main Authors: OLBERT, Peter Jochen, SCHRADER, Andres Jan, SIMON, Corinna, DALPKE, Alexander, BARTH, Peter, HOFMANN, Rainer, HEGELE, Axel
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - therapeutic use
Animals
Apoptosis
Biological and medical sciences
Carcinoma, Transitional Cell - genetics
Carcinoma, Transitional Cell - metabolism
Carcinoma, Transitional Cell - therapy
Female
Immunoenzyme Techniques
In Vitro Techniques
Interferon-gamma - genetics
Interferon-gamma - metabolism
Interleukin-10 - genetics
Interleukin-10 - metabolism
Interleukin-12 - genetics
Interleukin-12 - metabolism
Medical sciences
Mice
Mice, Inbred C3H
Nephrology. Urinary tract diseases
Oligodeoxyribonucleotides - therapeutic use
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
Tumor Cells, Cultured
Tumors
Tumors of the urinary system
Urinary Bladder - physiology
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - metabolism
Urinary Bladder Neoplasms - therapy
Urinary tract. Prostate gland
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Summary:Background: Intravesical BCG instillation is established and efficient in the prophylaxis of recurrent transitional cell carcinoma. A Th-1 biased immune response is postulated. Recent work has proven the efficacy of synthetic CpG-Oligodeoxynucleotides (ODN) as inducers and adjuvants for a strong Th1-response and there is evidence for a direct and/or adjuvant anti-neoplastic effect. The purpose of this study was to examine the local effects of CpG-ODN on the murine bladder wall after intravesical instillation and the effects on cytokine expression in an orthotopic murine bladder cancer model. Materials and Methods: Histopathology, immunohistochemistry and fluorescence microscopy were performed after different instillation schedules of stimulatory, non-stimulatory biotinylized and FITC-labelled CpG-ODN into the murine bladder. MB-49 murine bladder cancer cells were tested for TLR-9 expression to exclude a potential direct responsiveness to CpG-ODN. Furthermore induction of apoptosis was tested by annexin V staining and FACS analysis of CpG-ODN stimulated tumor cells. In an orthotopic C57/Bl6 murine bladder cancer model, the expressions of IL-12, IFNγ, IL-10 and TGF-β were evaluated after repeated CpG-ODN treatment. Results: Single and repeated instillation of CpG-ODN induced subepithelial and urothelial lymphocytic infiltrations with consecutive apoptoses. PBS and non-stimulative ODN induced no visible reaction. Bladder submucosa stained positive for biotin. Controls showed no endogenic biotin staining. FITC-labelled ODN adhered to the bladder mucosa and penetration of the mucosal barrier was not detected. MB-49 TCC cells did not express TLR-9 and CpG-ODN did not induce apoptosis in these cells. Repeated intravesical instillations of CpG-ODN in orthotopic murine tumor bearing urinary bladders resulted in significant up-regulation of both Th-1 and Th-2 cytokines. Conclusion: CpG-ODNs have promising anti-neoplastic potential. They exert a pronounced immunological response both in the native murine urinary bladder and in murine TCC. The mechanisms of action appear to be mediated immunologically, There was no direct effect of CpG-ODN on the tumor cells in this model.
ISSN:0250-7005
1791-7530