title: CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and β-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.
authors: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
authors: Wei
authors: W
authors: Mo
authors: Jian
authors: J
authors: Chen
authors: Amish
authors: A
authors: Patel
authors: Liang
authors: L
authors: Zhang
authors: Vincent
authors: V
authors: Chau
authors: Yanjiao
authors: Y
authors: Li
authors: Woosung
authors: W
authors: Cho
authors: Kyun
authors: K
authors: Lim
authors: Jing
authors: J
authors: Xu
authors: Alexander J
authors: AJ
authors: Lazar
authors: Chad J
authors: CJ
authors: Creighton
authors: Svetlana
authors: S
authors: Bolshakov
authors: Renée M
authors: RM
authors: McKay
authors: Dina
authors: D
authors: Lev
authors: Lu Q
authors: LQ
authors: Le
authors: Luis F
authors: LF
authors: Parada
mesh_terms: D019898:Autocrine Communication; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D018317:Nerve Sheath Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases