Conditional Inactivation ofPtenwithEGFROverexpression in Schwann Cells Models Sporadic MPNST

Vincent W Keng,Margaret H Collins,Kwangmin Choi,Nancy Ratner,Margaret R Wallace,Adrienne L Watson,Barbara R Tschida,Tilat A Rizvi,Branden S Moriarity,David A Largaespada,Hua Li,Eric P Rahrmann

doi:10.1155/2012/620834

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.

Highlights

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare aggressive form of sarcoma associated with poor prognosis
We have previously demonstrated the synergistic role of Pten inactivation to plexiform neurofibroma tumorigenesis and progression to high-grade PNSTs in the context of neurofibromatosis 1 (Nf1) loss in Schwann cells and/or their precursor cells [9]
We addressed the hypothesis that phosphatase and tensin homolog (PTEN) cooperates with epidermal growth factor receptor (EGFR) in the genetic evolution from a benign to malignant PNST

Summary

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare aggressive form of sarcoma associated with poor prognosis. Other than those at the neurofibromin 1 (NF1) locus, have rarely been detected in benign neurofibromas but are numerous in MPNSTs suggesting that many secondary genetic changes. Sarcoma are required for the transformation from a benign neurofibroma to MPNST. Mutations in rat sarcoma viral oncogene homolog (RAS) or its pathwayassociated genes may cause tumor initiation in sporadic MPNSTs that lack NF1 mutations. Activating mutations in RAS (NRAS or KRAS) or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations have been reported in sporadic MPNSTs [5, 6]. Many of the genetic alterations associated with MPNST initiation/progression are unknown, and identification of these genetic changes may have profound clinical benefits

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Conclusion