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Alveolar Type II Cells Isolated from Pulmonary Adenocarcinoma

A Model for JSRV Expression In Vitro

Université de Lyon; INRA, UMR754, Rétrovirus et Pathologie Comparée; Ecole Pratique des Hautes Etudes; IFR 128; Department of Respiratory Diseases, Reference Center for Orphan Lung Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon; and Ecole Nationale Vétérinaire de Lyon, Marcy L'Etoile, France

Correspondence and requests for reprints should be addressed to Caroline Leroux, UMR 754 INRA/ ENVL/UCBL, "Rétrovirus et Pathologie Comparée," IFR 128 BioSciences Lyon-Gerland, Université Claude Bernard, 50 avenue Tony Garnier, 69007 Lyon cedex 07, France. E-mail: caroline.leroux{at}univ-lyon1.fr

Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring cancer in sheep, with clinical, radiologic, and histopathologic features similar to that of human pneumonic-type bronchioloalveolar carcinoma. JSRV (Jaagsiekte Sheep RetroVirus) is the etiologic agent of this contagious lung cancer in sheep. Cells involved in the tumor derive from alveolar type II cells and Clara cells, epithelial cells of the distal respiratory tract. These cells are the major site for viral expression in JSRV-infected animals. Recent studies clearly described the oncogenic properties of the JSRV envelope protein both in vitro and in vivo. Interestingly, the cellular pathways involved in the transformation process seem to be dependent of the origin and type of the cell used. In order to investigate the specific interactions between JSRV and alveolar type II cells, we developed an in vitro experimental model in which lung epithelial cells were isolated from OPA and control lungs. Cells in culture expressed alveolar type II cell specific markers such as surfactant protein (SP)-A, SP-C, and a high alkaline phosphatase activity. Alveolar Type II cells derived from tumoral lungs showed a proliferative advantage and expressed the JSRV virus. The reverse transcriptase activity decreased over passages in monolayer culture conditions, but was efficiently maintained in three-dimensional culture conditions. We thus report on the first in vitro system whereby alveolar type II cells from OPA were efficiently maintained in culture and stably expressed JSRV. This novel experimental model will set up the stage for elucidating lung epithelial transformation in the JSRV-induced tumor.

Key Words: lung • JSRV • alveolar type II cell • pneumocyte • bronchioloalveolar carcinoma

CLINICAL RELEVANCE We describe a new in vitro model to study molecular mechanisms of tumoral transformation of type II pneumocytes.