Accession Number : ADA579784


Title :   The Mechanism by which Neurofibromin Suppresses Tumorigenesis


Descriptive Note : Annual summary rept. 1 February 2011-31 January 2013


Corporate Author : TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER


Personal Author(s) : Mo, Wei


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a579784.pdf


Report Date : Feb 2013


Pagination or Media Count : 31


Abstract : Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically and in a subset of patients with Neurofibromatosis type-1 (NF1) syndrome. 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 non-transformed precursor cells. In MPNSTs, high chemokine CXCR4 receptor and CXCL12 ligand levels promote tumor growth by stimulating cyclin D1 expression and cell cycle progression through PI3-kinase (PI3K) and -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 MPNST. Taken together, our findings indicate a role for CXCR4 in NF1-associated MPNST development, and identify a novel therapeutic target.


Descriptors :   *PERIPHERAL NEUROPATHY , CELLS(BIOLOGY) , CULTURES(BIOLOGY) , GENETICS , NEOPLASMS


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE