Abstract
BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed.MethodsThe effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model.ResultsThe results showed expression of platelet-derived growth factor receptor-β and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 − 4.6 μM) in three of six cell lines. Knockdown of PDGFR-β by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis.ConclusionsThe results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo.
Highlights
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis
We previously reported the identification of plateletderived growth factor-BB (PDGF-BB) as an MPNST cell invasion-inducing factor by profiling eight motogenic growth factors in two human MPNST cell lines [7]
Effects of Small interfering RNA (siRNA)-mediated inhibition of platelet-derived growth factor receptor-β (PDGFR-β) expression on MPNST cell growth To clarify the role of PDGFR-β in MPNST cell proliferation, we examined the effects of siRNA for PDGFR-β on cell proliferation in the two imatinib mesylate-sensitive cell lines (HS-Sch-2 and FMS-1), and on one resistant cell line (NMS-2PC)
Summary
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Half of the MPNST are found in patients with neurofibromatosis type 1 (NF1), while the rest develop de novo from peripheral nerves. The incidence of MPNST is 0.001% in the general population, but is as high as 2% to 13% in NF1 patients [3,4]. MPNST is a very aggressive tumor, with a high rate of local recurrence and. We demonstrated higher mRNA and proteins expression levels of platelet-derived growth factor receptor-β (PDGFR-β) in MPNST tissues than in benign peripheral nerve sheath tumors, such as schwannomas and neurofibromas. The results showed that PDGF-BB induced tyrosine phosphorylation of PDGFR-β, and that imatinib mesylate inhibited MPNST cell invasion and proliferation by suppressing the phosphorylation of PDGFR-β
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