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Therapeutic Potential of Replication-Selective Oncolytic Adenoviruses on Cells from Familial and Sporadic Desmoid Tumors

Authors' Affiliations: ¹ Institute of Cancer and the CR-UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom; ² Center for Human Genetics, Laboratorium voor moleculaire diagnostiek, Herestraat 49, Leuven, Belgium; ³ Polyposis Registry, CR-UK Colorectal Cancer Unit, St Mark's Hospital, Harrow, United Kingdom; ⁴ Bute Medical School, University of St Andrews, Fife, United Kingdom; and ⁵ Institut National de la Sante et de la Recherche Medicale, CIC-04 Biothérapies Hépatiques, CHU Hôtel Dieu; ⁶ Universite de Nantes, Nantes Atlantique Université, EA4274; and ⁷ Institut des Maladies de l'Appareil Digestif, CHU Hôtel Dieu, Nantes, France

Requests for reprints: Georges Vassaux, Institut National de la Sante et de la Recherche Medicale CIC-04, EA4274^ème étage HNB nord, CHU Hotel Dieu, 1 place Alexis Ricordeau, 44035 Nantes Cedex1, France. Phone: 33-240-087-508; Fax: 33-240-087-506; E-mail: georges.vassaux{at}nantes.inserm.fr.

Purpose: Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers and has been associated with familial and sporadic desmoid tumors. The aim of the present study is to assess the therapeutic potential of oncolytic adenoviruses selectively replicating in cells in which the Wnt signaling pathway is active on primary cells from desmoid tumors.

Experimental Design: Primary cells extracted from familial (n = 3) or sporadic (n = 3) desmoid tumors were cultured short term. Cancer cell survival and viral replication were measured in vitro upon infection with two different oncolytic adenoviruses targeting a constitutive activation of the Wnt signaling pathway. Adenoviral infectivity was also assessed.

Results: Although cells extracted from one sporadic desmoid tumor responded very well to the oncolytic action of the adenoviruses (<20% of viable cells upon infection at a multiplicity of infection of 10), cells from two tumor samples were totally resistant to the viral action. Cells from the remaining samples showed intermediate sensitivity to the oncolytic viruses. These effects were correlated to the level of infectivity of the cells. Finally, in responder cells, evidences of viral replication was observed.

Conclusions: Our experimental data suggest that the response of desmoid tumor cells to oncolytic adenovirus is neither correlated to the type of mutation activating the Wnt signaling pathway nor to the familial or sporadic nature of the tumor. In addition, they highlight the variability of infectivity of individual tumors and predict a great variability in the response to oncolytic adenoviruses.