Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested.


METHODS
We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines.


RESULTS
The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6.


CONCLUSIONS
Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials.
Monsurrò
Vladia
V
Department of Pathology, University of Verona Medical School, Verona, Italy.
Beghelli
Stefania
S
Wang
Richard
R
Barbi
Stefano
S
Coin
Silvia
S
Di Pasquale
Giovanni
G
Bersani
Samantha
S
Castellucci
Monica
M
Sorio
Claudio
C
Eleuteri
Stefano
S
Worschech
Andrea
A
Chiorini
Jay A
JA
Pederzoli
Paolo
P
Alter
Harvey
H
Marincola
Francesco M
FM
Scarpa
Aldo
A
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000502:physiology*; D007372:Interferons / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis / Q000379:methods; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018579:Patient Selection; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D034741:RNA, Small Interfering; D007372:Interferons