CpG-ODN increases the release of VEGF in a mouse model of lung carcinoma.
Vascular endothelial-derived growth factor (VEGF) plays a fundamental role in the formation of new vessels within the tumour mass. Increasing evidence has highlighted the involvement of Toll-like receptors (TLRs) in cancer. Of interest, TLR9 is over-expressed in human lung carcinoma tissues. The aim of our study was to determine whether TLR9 activation could alter VEGF release in a mouse model of lung carcinoma. Lewis lung carcinoma cells were intravenously (i.v.) inoculated and 10 days later, tumour-bearing mice were treated with CpG-ODN (CpG, a TLR9 ligand) or PBS. CpG administration enhanced VEGF release, which was associated with increased tumour lesions in the lung. CpG induced high levels of IL-6 expression and activation of STAT3 in tumour-bearing mice. Moreover, CpG induced VEGF release from primary fibroblasts and endothelial cells, which correlated with IL-6 and TGFβ production. This may explain the large influx of fibroblasts and the production of basic fibroblast growth factor (bFGF) in the tumour mass. The administration of a monoclonal antibody against VEGF A arrested tumour progression and induced a Th1-like response in CpG-treated tumour-bearing mice. In conclusion, our study demonstrates that the combination of CpG with anti-VEGF monoclonal antibody could be of potential therapeutic in lung carcinoma.
Sorrentino
Rosalinda
R
Department of Pharmaceutical Science, University of Salerno, Fisciano, Italy. rosalinda.sorrentino@googlemail.com
Morello
Silvana
S
Giordano
Maria Grazia
MG
Arra
Claudio
C
Maiolino
Piera
P
Adcock
Ian M
IM
Pinto
Aldo
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D018899:CpG Islands; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A