| First Author | Brosius SN | Year | 2014 |
| Journal | Acta Neuropathol | Volume | 127 |
| Issue | 4 | Pages | 573-91 |
| PubMed ID | 24232507 | Mgi Jnum | J:318855 |
| Mgi Id | MGI:6862561 | Doi | 10.1007/s00401-013-1209-3 |
| Citation | Brosius SN, et al. (2014) Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis. Acta Neuropathol 127(4):573-91 |
| abstractText | Malignant peripheral nerve sheath tumors (MPNSTs) are Schwann cell-derived malignancies that arise from plexiform neurofibromas in patients with mutation of the neurofibromin 1 (NF1) gene. We have shown that the growth factor neuregulin-1 (NRG1) also contributes to human neurofibroma and MPNST pathogenesis and that outbred C57BL/6J x SJL/J transgenic mice overexpressing NRG1 in Schwann cells (P0-GGFbeta3 mice) recapitulate the process of neurofibroma-MPNST progression. However, it is unclear whether NRG1 acts predominantly within NF1-regulated signaling cascades or instead activates other essential cascades that cooperate with NF1 loss to promote tumorigenesis. We now report that tumorigenesis is suppressed in inbred P0-GGFbeta3 mice on a C57BL/6J background. To determine whether NRG1 overexpression interacts with reduced Nf1 or Trp53 gene dosage to "unmask" tumorigenesis in these animals, we followed cohorts of inbred P0-GGFbeta3;Nf1+/-, P0-GGFbeta3;Trp53+/- and control (P0-GGFbeta3, Nf1+/- and Trp53+/-) mice for 1 year. We found no reduction in survival or tumors in control and P0-GGFbeta3;Nf1+/- mice. In contrast, P0-GGFbeta3;Trp53+/- mice died on average at 226 days, with MPNSTs present in 95 % of these mice. MPNSTs in inbred P0-GGFbeta3;Trp53+/- mice arose de novo from micro-MPNSTs that uniformly develop intraganglionically. These micro-MPNSTs are of lower grade (WHO grade II-III) than the major MPNSTs (WHO grade III-IV); array comparative genomic hybridization showed that lower grade MPNSTs also had fewer genomic abnormalities. Thus, P0-GGFbeta3;Trp53+/- mice represent a novel model of low- to high-grade MPNST progression. We further conclude that NRG1 promotes peripheral nervous system neoplasia predominantly via its effects on the signaling cascades affected by Nf1 loss. |
