Pancreatic adenocarcinoma (PDAC) is a leading and increasing cause of cancer mortality for which no effective therapy is available. Thus, novel therapeutic approaches such as gene therapy are being tested for direct delivery of pro-apoptotic signals, for the modulation of tumor microenvironment or for directly induce oncolysis. Those approaches often rely on tumor-tropic viruses such as adenoviruses. Applying global transcriptional profiling, we observed two clearly distinguishable phenotypes of human PDAC according to their constitutive expression of interferon (IFN)-stimulated genes (ISGs) in vitro and in vivo. The findings were validated in human samples as well as primary PDAC-derived xenografts by testing in tissue arrays the expression of the Myxovirus-resistance A (MxA) gene, a protein which best represents the down-stream activation of IFN dependent pathways. Most importantly, two patterns of MxA expression could also be observed in tissues from primary PDACs suggesting that the discovered phenotype represents distinct natural behaviours of the disease. To test whether ISG-expression in PDACs confers an anti-viral activity, we subsequently transfected PDAC cell lines with the GFP or luciferase-expressing adenovirus (Ad5-CMV-GFP or Ad5-CMV-Luc) and observed significant reduced GFP expression in ISG-expressing cell lines suggesting a potential resistance to adenoviral infection. Similar findings could be observed infecting cells with luciferase expressing Adeno-Associated Viruses 5 and 6 (AAV5-CMV-luc and AAV6-CMV-luc) as well as at the lytic level using a wilde type form of adenovirus. Those finding are giving a more comprehensive meaning to our finding. Thus, this study identified two PDAC phenotypes that display different permissivity to virus that are commonly used for gene therapy and oncolytic therapies. Furthermore, although no correlation was noted between ISG expression and natural history of disease, this two phenotypes may be differentially susceptible to virally mediated gene therapy and may, therefore, affect long term the outcome of the disease in response to tailored gene therapy efforts as well as interfere with possible cancer immunotherapeutic trials.

Anti-viral phenotype of pancreatic adenocarcinoma: potential relevance for gene therapy

MONSURRO', Vladia
2009-01-01

Abstract

Pancreatic adenocarcinoma (PDAC) is a leading and increasing cause of cancer mortality for which no effective therapy is available. Thus, novel therapeutic approaches such as gene therapy are being tested for direct delivery of pro-apoptotic signals, for the modulation of tumor microenvironment or for directly induce oncolysis. Those approaches often rely on tumor-tropic viruses such as adenoviruses. Applying global transcriptional profiling, we observed two clearly distinguishable phenotypes of human PDAC according to their constitutive expression of interferon (IFN)-stimulated genes (ISGs) in vitro and in vivo. The findings were validated in human samples as well as primary PDAC-derived xenografts by testing in tissue arrays the expression of the Myxovirus-resistance A (MxA) gene, a protein which best represents the down-stream activation of IFN dependent pathways. Most importantly, two patterns of MxA expression could also be observed in tissues from primary PDACs suggesting that the discovered phenotype represents distinct natural behaviours of the disease. To test whether ISG-expression in PDACs confers an anti-viral activity, we subsequently transfected PDAC cell lines with the GFP or luciferase-expressing adenovirus (Ad5-CMV-GFP or Ad5-CMV-Luc) and observed significant reduced GFP expression in ISG-expressing cell lines suggesting a potential resistance to adenoviral infection. Similar findings could be observed infecting cells with luciferase expressing Adeno-Associated Viruses 5 and 6 (AAV5-CMV-luc and AAV6-CMV-luc) as well as at the lytic level using a wilde type form of adenovirus. Those finding are giving a more comprehensive meaning to our finding. Thus, this study identified two PDAC phenotypes that display different permissivity to virus that are commonly used for gene therapy and oncolytic therapies. Furthermore, although no correlation was noted between ISG expression and natural history of disease, this two phenotypes may be differentially susceptible to virally mediated gene therapy and may, therefore, affect long term the outcome of the disease in response to tailored gene therapy efforts as well as interfere with possible cancer immunotherapeutic trials.
pancreatic adenocarcinoma; gene therapy; tumor immunology
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/339559
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