cyclin-d1 and Peripheral-Nervous-System-Neoplasms

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors, accounting for around 5% of all soft tissue sarcomas. A better understanding of the pathogenesis of these tumors and the development of effective treatments are needed. In this context, established tumor cell lines can be very informative, as they may be used for in-depth molecular analyses and improvement of treatment strategies. Here, we present the genomic and transcriptomic profiling analysis of a MPNST cell line (BL1391) that was spontaneously established in our laboratory from a primary tumor that had not been exposed to genotoxic treatment. This cell line shows peculiar genetic features, such as a large marker chromosome composed of high-copy number amplifications of regions from chromosomes 1 and 11 with an embedded neocentromere. Moreover, the transcriptome profiling revealed the presence of several fusion transcripts involving the CACHD1, TNMA4, MDM4, and YAP1 genes, all of which map to the amplified regions of the marker. BL1391 could be a useful tool to study genomic amplifications and neocentromere seeding in MPNSTs and to develop new therapeutic strategies.

Topics: Adaptor Proteins, Signal Transducing; Aged, 80 and over; Cell Cycle Proteins; Cell Line, Tumor; Cyclin D1; Cyclin-Dependent Kinase 4; Female; Gene Amplification; Gene Expression Profiling; Humans; Membrane Proteins; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Proto-Oncogene Proteins; Transcription Factors; YAP-Signaling Proteins

Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1-MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically-targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/Protein Kinase-B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1-associated, and likely sporadic, MPNSTs.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cyclin D1; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neurofibromatosis 1; Peripheral Nervous System Neoplasms; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Young Adult