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1.
BMC Res Notes ; 11(1): 520, 2018 Jul 28.
Article in English | MEDLINE | ID: mdl-30055648

ABSTRACT

OBJECTIVE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas characterized by high recurrence rates and early metastases. These tumors arise more frequently within neurofibromatosis type 1 (NF1) and present with resistance during standard chemotherapy leading to increased mortality and morbidity in those patients. In vitro all-trans retinoic acid (ATRA) and MEK inhibitors (MEKi) were shown to inhibit tumor proliferation, especially when applied in combination. Therefore, we established a nude mouse model to investigate if treatment of xenografts derived from NF1 associated S462 and T265 MPNST cells respond to ATRA and the MEKi PD0325901. RESULTS: We demonstrated that human NF1 associated MPNST derived from S462 but not T265 cells form solid subcutaneous tumors in Foxn1 nude mice but not in Balb/c, SHO or Shorn mice. We verified a characteristic staining pattern of human MPNST xenografts by immunohistochemistry. Therapeutic effects of ATRA and/or MEKi PD0325901 on growth of S462 MPNST xenografts in Foxn1 nude mice were not demonstrated in vitro, as we did not observe significant suppression of MPNST growth compared with placebo treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Diphenylamine/analogs & derivatives , Nerve Sheath Neoplasms/drug therapy , Sarcoma/drug therapy , Animals , Diphenylamine/pharmacology , Heterografts , Humans , Mice , Mice, Nude , Neurilemmoma
2.
Am J Pathol ; 186(12): 3285-3296, 2016 12.
Article in English | MEDLINE | ID: mdl-27765635

ABSTRACT

Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.


Subject(s)
Nerve Sheath Neoplasms/genetics , Neurilemmoma/genetics , Neurofibroma/genetics , Neurofibromatoses/genetics , Neurofibromatosis 1/genetics , Skin Neoplasms/genetics , alpha Catenin/genetics , Adolescent , Adult , Aged , Chromosomes, Human, Pair 22/genetics , Comparative Genomic Hybridization , Epithelial-Mesenchymal Transition , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Monosomy , Nerve Sheath Neoplasms/pathology , Neurilemmoma/pathology , Neurofibroma/pathology , Neurofibromatoses/pathology , Neurofibromatosis 1/pathology , Schwann Cells/metabolism , Schwann Cells/pathology , Skin Neoplasms/pathology , Tumor Suppressor Proteins/genetics , Young Adult
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