SV40-Dependent AKT Activity Drives Mesothelial Cell Transformation after Asbestos Exposure
Wednesday, June 15th, 2005.
Cancer Research 65, 5256-5262, June 15, 2005 [Link]
Paola Cacciotti1, Dario Barbone1, Camillo Porta2, Deborah A. Altomare4,
Joseph R. Testa4, Luciano Mutti3 and
Giovanni Gaudino1
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
Abstract
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.
Glossary
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- antigen
- (an-tuh-jen) a substance that causes the body's immune system to react. This reaction often involves production of antibodies. For example, the immune system's response to antigens that are part of bacteria and viruses helps people resist infections. Cancer cells have certain antigens that can be found by laboratory tests. They are important in cancer diagnosis and in watching response to treatment. Other cancer cell antigens play a role in immune reactions that may help the body's resistance against cancer.
- virus
- very small organisms that cause infections. Viruses are too small to be seen with a regular microscope. They reproduce only in living cells.
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
