Conditional Inactivation ofPtenwithEGFROverexpression in Schwann Cells Models Sporadic MPNST

[摘要] 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 bothphosphatase and tensin homolog(PTEN) andepidermal growth factor receptor(EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs,PTENexpression is often reduced, whileEGFRexpression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles ofPten, andEGFRwas expressed under the control of the 2′,3′-cyclic nucleotide3′phosphodiesterase(Cnp) promoter and adesert hedgehog(Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss ofPtenandEGFRoverexpression in Schwann cells led to the development of high-grade PNSTs.In vitroexperiments using immortalized human Schwann cells demonstrated that loss ofPTENand overexpression ofEGFRcooperate 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.

[学科分类] 肿瘤学