RESUMO
BACKGROUND AND PURPOSE: Thalamic hypometabolism is a consistent finding in brain PET with F-18 fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1). However, the pathophysiology of this metabolic alteration is unknown. We hypothesized that it might be secondary to disturbance of peripheral input to the thalamus by NF1-characteristic peripheral nerve sheath tumors (PNSTs). To test this hypothesis, we investigated the relationship between thalamic FDG uptake and the number, volume, and localization of PNSTs. METHODS: This retrospective study included 22 adult NF1 patients (41% women, 36.2 ± 13.0 years) referred to whole-body FDG-PET/contrast-enhanced CT for suspected malignant transformation of PNSTs and 22 sex- and age-matched controls. Brain FDG uptake was scaled voxelwise to the individual median uptake in cerebellar gray matter. Bilateral mean and left-right asymmetry of thalamic FDG uptake were determined using a left-right symmetric anatomical thalamus mask. PNSTs were manually segmented in contrast-enhanced CT. RESULTS: Thalamic FDG uptake was reduced in NF1 patients by 2.0 standard deviations (p < .0005) compared to controls. Left-right asymmetry was increased by 1.3 standard deviations (p = .013). Thalamic hypometabolism was higher in NF1 patients with ≥3 PNSTs than in patients with ≤2 PNSTs (2.6 vs. 1.6 standard deviations, p = .032). The impact of the occurrence of paraspinal/paravertebral PNSTs and of the mean PNST volume on thalamic FDG uptake did not reach statistical significance (p = .098 and p = .189). Left-right asymmetry of thalamic FDG uptake was not associated with left-right asymmetry of PNST burden (p = .658). CONCLUSIONS: This study provides first evidence of left-right asymmetry of thalamic hypometabolism in NF1 and that it might be mediated by NF1-associated peripheral tumors.
Assuntos
Neoplasias de Bainha Neural , Neurofibromatose 1 , Adulto , Humanos , Feminino , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18/metabolismo , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/metabolismo , Estudos Retrospectivos , Carga Tumoral , Tomografia por Emissão de Pósitrons/métodos , Neoplasias de Bainha Neural/complicações , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Tálamo/diagnóstico por imagem , Tálamo/patologiaRESUMO
OBJECTIVE: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model. RESULTS: We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.
Assuntos
Neoplasias de Bainha Neural , Neurofibroma Plexiforme , Neurofibroma , Neurofibromatose 1 , Humanos , Gravidez , Feminino , Animais , Camundongos , Neurofibromatose 1/genética , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Ácido Fólico , Neurofibroma/complicações , Neurofibroma/patologia , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/patologiaRESUMO
BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. METHODS: We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography - tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. RESULTS: Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. CONCLUSIONS: We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST.
Assuntos
Neoplasias de Bainha Neural , Neurofibrossarcoma , Humanos , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/genética , Proteoma , Avaliação Pré-Clínica de Medicamentos , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Proteômica , Linhagem Celular TumoralRESUMO
BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. The malignant peripheral nerve sheath tumor (MPNST), transformed from NF1 related plexiform neurofibroma, is a rapidly growing and highly invasive tumor. No effective chemotherapeutic agent is currently available. Calebin-A is a derivative from turmeric Curcuma longa. Given the anti-inflammatory and anticancer potentials of curcumin, whether Calebin-A also had the tumoricidal effect upon MPNST cells is still elusive. PURPOSE: To determine whether Calebin-A has the potential for anti-MPNST effect. METHODS: The MTT and FACS analysis of normal Schwann (HSC) and MPNST cells have been employed to determine the tumoricidal effect of Calebin-A. The expression of the signal pathway molecules was assessed by Western blotting. The CHIP with quantitative PCR assay was performed to quantify the promoter DNA binding to acetylated histone 3 (acetyl H3). The enzyme activities of histone acetyltransferase (HAT) and deacetylase (HDAC) have been evaluated by commercial kits. The measurements of tumor size of the xenograft mouse model were also performed. RESULTS: Calebin-A inhibited the proliferation of MPNST and primary neurofibroma cells in a dose-dependent manner. The flow cytometry analysis of the MPNST cells after treatment of 25⯵m of Calebin-A demonstrated an increase of population in the G0/G1 phase but decrease in G2/M phase. Before treatment, the expression of Axl, Tyro3, and acetyl H3 was significantly higher in MPNST cells when compared to HSC. The expression of phosphorylated-AKT, -ERK1/2, survivin, hTERT, and acetyl H3 proteins were reduced after treatment. The CHIP assay shows the promoter DNA copies of survivin (BRIC5) and hTERT genes are significantly reduced post-treatment. The enzyme activity of HAT was significantly reduced, but not that of HDAC. Two HAT inhibitors, epigallocatechin-3-gallate (EGCG) and anacardic acid (AA) have also demonstrated a significant inhibitory effect on MPNST cells. Finally, the measurements of tumor size showed a significant reduction of the xenograft tumors after treatment of Calebin-A. CONCLUSION: Both in vitro and in vivo studies showed Calebin-A could inhibit the proliferation of MPNST with suppression of survivin and hTERT. The reduced expression of these two factors might be through the epigenetic histone modification resulting from the decreased activity of HAT.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cinamatos/farmacologia , Histona Acetiltransferases/metabolismo , Monoterpenos/farmacologia , Neoplasias de Bainha Neural/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neoplasias de Bainha Neural/enzimologia , Neoplasias de Bainha Neural/patologia , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Survivina/genética , Survivina/metabolismo , Telomerase/genética , Telomerase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of soft tissue neoplasm with extremely poor prognosis and no effective medical options currently available. MPNSTs can occur either sporadically or in association with the neurofibromatosis type 1 (NF1) syndrome. Importantly, activation of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and WNT/CTNNB1 signaling pathways has been reported in both NF1-related and late-stage sporadic MPNSTs. In this study, we found that DAW22, a natural sesquiterpene coumarin compound isolated from Ferula ferulaeoides (Steud.) Korov., could inhibit cell proliferation and colony formation in five established human MPNST cancer cell lines. Further molecular mechanism exploration indicated that DAW22 could target the main components in the MPNST tumorigenic pathways: namely suppress phosphorylation of AKT and ERK, and reduce levels of non-phospho (active) CTNNB1. Using the xenograft mouse model transplanted with human MPNST cancer cell line, daily treatment with DAW22 for 25 days was effective in reducing tumor growth. These results support DAW22 as an alternative therapeutic compound for MPNST treatment by affecting multiple signaling transduction pathways in its disease progression.
Assuntos
Cumarínicos/farmacologia , Neoplasias de Bainha Neural/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Modelos Animais de Doenças , Camundongos , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/patologia , Fosforilação , Sesquiterpenos/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.
Assuntos
Cantaridina/uso terapêutico , Nifedipino/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Cantaridina/efeitos adversos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Nus , Neoplasias de Bainha Neural/tratamento farmacológico , Neurofibromatose 1 , Nifedipino/efeitos adversos , Proteína Fosfatase 2/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare highly aggressive sarcomas that affect 8-13% of people with neurofibromatosis type 1. The prognosis for patients with MPNST is very poor. Despite TOP2A overexpression in these tumors, doxorubicin resistance is common, and the mechanisms of chemotherapy resistance in MPNST are poorly understood. Molecular-guided therapy prediction is an emerging strategy for treatment refractory sarcomas that involves identification of therapy response and resistance mechanisms in individual tumors. Here, we report the results from a personalized, molecular-guided therapy analysis of MPNST samples. METHODS: Established molecular-guided therapy prediction software algorithms were used to analyze published microarray data from human MPNST samples and cell lines, with benign neurofibroma tissue controls. MPNST and benign neurofibroma-derived cell lines were used for confirmatory in vitro experimentation using quantitative real-time PCR and growth inhibition assays. Microarray data was analyzed using Affymetrix expression console MAS 5.0 method. Significance was calculated with Welch's t-test with non-corrected p-value < 0.05 and validated using permutation testing across samples. Paired Student's t-tests were used to compare relative EC50 values from independent growth inhibition experiments. RESULTS: Molecular guided therapy predictions highlight substantial variability amongst human MPNST samples in expression of drug target and drug resistance pathways, as well as some similarities amongst samples, including common up-regulation of DNA repair mechanisms. In a subset of MPNSTs, high expression of ABCC1 is observed, serving as a predicted contra-indication for doxorubicin and related therapeutics in these patients. These microarray-based results are confirmed with quantitative, real-time PCR and immunofluorescence. The functional effect of drug efflux in MPNST-derived cells is confirmed using in vitro growth inhibition assays. Alternative therapeutics supported by the molecular-guided therapy predictions are reported and tested in MPNST-derived cells. CONCLUSIONS: These results confirm the substantial molecular heterogeneity of MPNSTs and validate molecular-guided therapy predictions in vitro. The observed molecular heterogeneity in MPNSTs influences therapy prediction. Also, mechanisms involving drug transport and DNA damage repair are primary mediators of MPNST chemotherapy resistance. Together, these findings support the utility of individualized therapy in MPNST as in other sarcomas, and provide initial proof-of concept that individualized therapy prediction can be accomplished.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Terapia de Alvo Molecular , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Medicina de PrecisãoRESUMO
PURPOSE: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. EXPERIMENTAL DESIGN: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. RESULTS: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. CONCLUSIONS: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias de Bainha Neural/tratamento farmacológico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Feminino , Flavonoides/administração & dosagem , Humanos , Immunoblotting , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Gradação de Tumores , Piperidinas/administração & dosagem , Distribuição TecidualRESUMO
Malignant schwannomas or malignant peripheral nerve sheath tumors (MPNST) represent approximately 10% of all soft tissue sarcomas. Metastatic disease from chest wall MPNST is very rare. We present a case of a major clinical response to the tyrosine kinase inhibitor (TKI) sorafenib in a patient with metastatic MPNST. A 42-year-old female with a prior history of neurofibromas developed MPNST, which later metastasized to the lungs and brain. She was initially placed on sorafenib with significant clinical response to lung metastases. MPNST show high levels of Ras activity and hence these tumors are promising targets for TKIs. Studies are ongoing and the results are eagerly awaited regarding the responses to these medications and whether they can positively impact on the natural history of this disease.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/tratamento farmacológico , Neurilemoma/diagnóstico , Neurilemoma/tratamento farmacológico , Piridinas/uso terapêutico , Parede Torácica/patologia , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Imageamento por Ressonância Magnética , Metástase Neoplásica , Neoplasias de Bainha Neural/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/uso terapêutico , Radiografia Torácica , Sorafenibe , Resultado do TratamentoRESUMO
We report a case of an intraneural perineurioma that developed in an unusual location, the tongue. A 16-year-old male presented with a 1 cm sized protruding submucosal mass in his tongue without any sensory or motor signs or symptoms. The mass was excised. The mucosa was intact, with an ill-defined firm mass measuring 1.0 x 0.8 x 0.6 cm in the submucosa and muscle. The cut surface of the mass was pinkish gray and fibrotic. Microscopically, the mass contained tortuous and thickened peripheral nerve bundles in the submucosa, showing onion bulb like structures. The onion bulb like structures consisted of centrally located S-100 protein positive Schwann cells surrounded by Glut-1 positive perineurial cells. The FISH study did not reveal any genetic aberrations in chromosome 22.
Assuntos
Adolescente , Humanos , Masculino , Cromossomos Humanos Par 22 , Genes da Neurofibromatose 2 , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Mucosa , Neoplasias de Bainha Neural , Cebolas , Nervos Periféricos , Proteínas S100 , Células de Schwann , Neoplasias da Língua , LínguaRESUMO
There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.
Assuntos
Antimitóticos/farmacologia , Ciclina D1/metabolismo , Neurofibromatose 1/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Zanthoxylum/química , Animais , Antimitóticos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neoplasias de Bainha Neural/patologia , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Fitoterapia , Extratos Vegetais/uso terapêutico , Transdução de Sinais , Transplante Heterólogo , Quinases Ativadas por p21RESUMO
Malignant peripheral nerve sheath tumors are rare spindle-cell sarcomas derived from Schwann cells or pluripotent cells of the neural crest. They arise from the spinal roots, peripheral nerves, brachial and lumbosacral plexi, cranial nerves and terminal nerve fibers within soft tissue, intestine, lung and bone. These tumors recur either locally, or metastasize distally. Most of these tumors occur in association with neurofibromatosis type 1. Spinal cord metastasis from malignant nerve sheath tumors associated with neurofibromatosis type 1 is very rare. We describe a rare case of near-total spinal cord metastasis in a patient with malignant nerve sheath tumor in the absence of neurofibromatosis, and highlight the microscopic findings and natural history of this disease process.
Assuntos
Neoplasias Pulmonares/secundário , Neoplasias de Bainha Neural/patologia , Neurofibroma/patologia , Neoplasias da Medula Espinal/secundário , Adulto , Benzenossulfonatos/uso terapêutico , Quimioterapia Adjuvante , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/terapia , Imageamento por Ressonância Magnética , Neoplasias de Bainha Neural/cirurgia , Neurofibroma/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/uso terapêutico , Sorafenibe , Neoplasias da Medula Espinal/terapiaRESUMO
Neurofibromatosis type 1 (NF1) is a common genetic disorder of the nervous system resulting in neurofibromas and malignant peripheral nerve sheath tumors (MPNST). In this study, we report the modulation of murine and human MPNST cell growth by the fatty acids docosahexaenoic acid (DHA) and arachidonic acid (AA). DHA demonstrated a tendency to stimulate cell growth at low doses and induce apoptosis at high doses, paralleled by the activation of ERK and caspase-3. Furthermore, high-dose DHA reversed the stimulation of MPNST cell growth by a number of growth factors suggested to have a pathogenic effect in NF1 and inhibited MPNST growth in vivo. AA was found to have a reciprocal activity in vitro, stimulating MPNST cell growth at comparable concentrations and reducing DHA activation of ERK. These findings introduce fatty acids as a possible regulator of MPNST development in NF1 patients.