tretinoin and Neurilemmoma

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms that commonly occur in patients with neurofibromatosis type 1 (NF1). Effective chemotherapy is not available. To characterize a therapeutic target for treatment, we investigated the role of cellular retinoic acid binding protein 2 (CRABP2) in MPNST in vitro. CRABP2 is a transcriptional co-activator of retinoic acid signaling. Although overexpression of CRABP2 is described in several cancers, it has not yet been studied in MPNSTs. We investigated CRABP2 expression in cultured Schwann cells and formalin-fixed, paraffin-embedded specimens of human peripheral nerve sheath tumors. A transient knockdown of CRABP2 was established in human NF1-associated MPNST cell lines (S462, T265, NSF1), and functional effects on viability, proliferation, apoptosis, and cytotoxicity were monitored. Finally, a 45-pathway reporter assay was performed in knockdown cells. Expression of CRABP2 was found in epithelium, fibroblasts, and tumor Schwann cells of skin, neurofibromas, and MPNSTs. In contrast, normal skin Schwann cells (NF1

Topics: Apoptosis; Carcinogenesis; Cell Proliferation; Cell Survival; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genes, Reporter; Humans; Nerve Sheath Neoplasms; Neurilemmoma; Neurofibroma; Neurofibromatosis 1; Receptors, Retinoic Acid; Schwann Cells; Signal Transduction; Tretinoin; Up-Regulation

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by an increased risk of malignant peripheral nerve sheath tumors (MPNST). Chemotherapy of MPNST is still insufficient. In this study, we investigated whether human tumor Schwann cells derived from NF1 associated MPNST respond to all-trans retinoic acid (ATRA). We analyzed effects of ATRA and MEK inhibitor (MEKi) combination therapy.. MPNST cell lines S462, T265, NSF1 were treated with ATRA and MEKi U0126 and PD0325901. We assessed cell viability, proliferation, migration, apoptosis and differentiation as well as mRNA expression of RAR and RXR subtypes and ATRA target genes such as CRABP2, CYP26A1, RARB and PDK1. We also analyzed CRABP2 methylation in cell lines and performed immunohistochemistry of human MPNST specimens.. ATRA therapy reduced viability and proliferation in S462 and T265 cells, accompanied by differentiation, apoptosis and reduced migration. NSF1 cells which lacked RXRG expression did not respond to ATRA. We furthermore demonstrated that ATRA signaling was functional for common targets, and that mRNA expression of CRABP2 and its targets was raised by ATRA therapy, whereas alternative pathways via FABP5 were not induced. Finally, combination of ATRA and MEKi demonstrated additively reduced viability of T265 and S462 cells.. We observed therapeutic effects in two of three MPNST cell lines pronounced by combination therapy. These data point to a potentially successful treatment of MPNST by combined application of ATRA and MEK inhibitors such as U0126 or PD0325901.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Therapy, Combination; Gene Expression Profiling; Humans; MAP Kinase Kinase Kinases; Methylation; Neurilemmoma; Neurofibromatosis 1; Protein Kinase Inhibitors; Rats; Signal Transduction; Tretinoin