Differential modulation of malignant peripheral nerve sheath tumor growth by omega-3 and omega-6 fatty acids.

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.

Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by systemic development of neurofibromas. Early clinical diagnosis can be ambiguous, and genetic diagnosis can be prohibitively difficult. Dysregulation of a number of growth factors has been suggested to be a mechanism of pathogenesis. This study was performed to assess the contribution of circulating growth factors for diffuse tumorigenesis and the diagnostic value of circulating growth factor identification in serum. EXPERIMENTAL DESIGN: The growth stimulation of neurofibroma-derived cells by serum from NF1 patients was tested, and serum growth factor levels in a cohort of NF1 patients (n = 39) between the ages of 7 and 70 years were analyzed. RESULTS: Concentrations of midkine (MK) and stem cell factor, but not epidermal growth factor, were substantially increased in serum of NF1 patients when compared with healthy controls. Within the NF1 group, MK levels increased dramatically at puberty from an average of 0.79 ng/mL in patients <18 years to 1.18 ng/mL in patients >18 years old. Stem cell factor and MK concentrations above a defined threshold in serum of NF1 patients are of diagnostic benefit for 96% of patients in the cohort tested. Furthermore, serum from NF1 patients enhanced proliferation of human neurofibroma-derived primary Schwann cells and endothelial cells substantially better than normal serum. CONCLUSIONS: Enhanced circulating growth factor levels contribute to diffuse tumorigenesis in NF1 and may provide the basis for molecular diagnosis.