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Sarcoma
Volume 2012 (2012), Article ID 620834, 12 pages
http://dx.doi.org/10.1155/2012/620834
Research Article

Conditional Inactivation of Pten with EGFR Overexpression in Schwann Cells Models Sporadic MPNST

1Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
2Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
3Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
4Brain Tumor Program, University of Minnesota, Minneapolis, MN 55455, USA
5Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
6Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA
7Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
8Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
9UF Shands Cancer Center, Genetics Institute, University of Florida, Gainesville, FL 32610, USA
10Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA

Received 6 August 2012; Accepted 2 November 2012

Academic Editor: R. Pollock

Copyright © 2012 Vincent W. Keng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2′,3′-cyclic nucleotide 3′phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.