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Cell and Tumor Biology |
1 Department of Medical Sciences, University of Piemonte Orientale A. Avogadro, Novara, Italy; 2 IRCCS Policlinico San Matteo University Hospital; 3 IRCSS Maugeri Foundation, Pavia, Italy; and 4 Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Requests for reprints: Giovanni Gaudino, Department of Medical Sciences, Via Solaroli, 17-28100 Novara, Italy. Phone: 39-0321-660631; Fax: 39-0321-620421; E-mail: giovanni.gaudino{at}unipmn.it.
Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.
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