This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Altomare, D. A. Articles by Testa, J. R. Search for Related Content PubMed PubMed Citation Articles by Altomare, D. A. Articles by Testa, J. R.

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

¹ Human Genetics Program and ² Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ³ Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island; ⁴ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁵ Department of Pathology, MGH Cancer Center and Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Joseph R. Testa, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-2610; Fax: 215-214-1623; E-mail: joseph.testa{at}fccc.edu.

Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/–) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/–) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/–) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/–) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/–) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.

This article has been cited by other articles:

				M. L. De Bruin, J. A. Burgers, P. Baas, M. B. van 't Veer, E. M. Noordijk, M. W. J. Louwman, J. M. Zijlstra, H. van den Berg, B. M. P. Aleman, and F. E. van Leeuwen Malignant mesothelioma after radiation treatment for Hodgkin lymphoma Blood, April 16, 2009; 113(16): 3679 - 3681. [Abstract] [Full Text] [PDF]

				D. A. Altomare, C. W. Menges, J. Pei, L. Zhang, K. L. Skele-Stump, M. Carbone, A. B. Kane, and J. R. Testa Activated TNF-{alpha}/NF-{kappa}B signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice PNAS, March 3, 2009; 106(9): 3420 - 3425. [Abstract] [Full Text] [PDF]

				T. Yokoyama, H. Osada, H. Murakami, Y. Tatematsu, T. Taniguchi, Y. Kondo, Y. Yatabe, Y. Hasegawa, K. Shimokata, Y. Horio, et al. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation Carcinogenesis, November 1, 2008; 29(11): 2139 - 2146. [Abstract] [Full Text] [PDF]

				H. L. Kindler, R. Bueno, and J. R. Testa New Biomarkers, Surgical Controversies, and Rationally Targeted Therapies for Malignant Mesothelioma ASCO Educational Book, January 1, 2008; 2008(1): 354 - 361. [Abstract] [Full Text] [PDF]