Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberrant CD44 expression.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies that arise within peripheral nerves. These tumors occur with increased incidence in patients with neurofibromatosis type 1 (NF1), exhibiting increased Ras activity due to loss of the NF1 gene product, neurofibromin, and abnormal expression of the epidermal growth factor receptor (EGFR). We previously found that MPNSTs express increased levels of the CD44 family of transmembrane glycoproteins that have been implicated in tumor cell invasion and metastasis. In two MPNST cell lines, we have found that elevated CD44 expression and cell invasion are dependent on Src kinase activity but are independent of mitogen-activated protein kinases (MAPK) kinase (MEK) activity. In contrast, inhibition of Src kinase activity has no influence on MPNST cell proliferation. Reduction of CD44 levels, using antisense oligonucleotides, results in reduced MPNST cell invasion in vitro, suggesting that Src contributes in part to MPNST cell invasion by increasing CD44 levels. At least some of this increased CD44 expression results from elevated EGFR levels through a Src-dependent mechanism, consistent with the notion that EGFR promotes constitutive Src activation in MPNSTs. These data indicate that Src and CD44 are putative targets for the treatment of MPNST invasion and metastasis.
Su
Weiping
W
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Sin
Mihaela
M
Darrow
Andrea
A
Sherman
Larry S
LS
D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D018317:Nerve Sheath Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D017253:Neurofibromatoses / Q000201:enzymology* / Q000503:physiopathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000201:enzymology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D066246:ErbB Receptors; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human