Overexpression of the lysophosphatidic acid generating enzyme autotaxin/ENPP2 potentially promotes the pathogenesis of neurofibromatosis type 1‐associated neurofibromas and malignant peripheral nerve sheath tumors
Abstract
Aggressive Schwann cell‐derived sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1 (NF1). It has been proposed that growth factors such as lysophosphatidic acid (LPA) interact with NF1 loss to drive MPNST pathogenesis. LPA promotes Schwann cell proliferation, migration and survival; LPA induced proliferation and survival is further enhanced in Nf1−/− Schwann cells. As autotaxin (ATX)/ENPP2, the enzyme that generates LPA via conversion of lysophosphatidylcholine, is overexpressed in several other tumor types, we hypothesized that ATX overexpression promotes the pathogenesis of MPNSTs and the benign neurofibromas from which they are derived. To test this hypothesis, we examined ATX expression in human neurofibromas, MPNSTs and MPNST cell lines and MPNSTs arising in a novel mouse model (P0‐GGFβ3 mice). Immunohistochemical studies showed that ATX was overexpressed in human and murine tumors compared to normal nerve. Real time PCR and immunoblots further demonstrated increased ATX expression in a panel of MPNST cell lines; the ATX transcripts present in these cells encoded several functionally distinct splice variants of ATX including α, β and γ isoforms. We are currently knocking down ATX expression and generating ATX overexpressing transgenic mice to validate ATX as a therapeutic target in MPNSTs. Funded by NIH and DOD.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2013
- Source ID
- 10.1096/fasebj.27.1_supplement.53.5
Entities
People
- Kevin A. Roth
- Lafe Timothy Peavler
- Stephanie J. Byer
- Steven L. Carroll
Organizations
- National Institutes of Health
- United States Department of Defense
- University of Alabama at Birmingham