Neurofibroma-derived Schwann cells hyperproliferate in response to progesterone

Objectives: Neurofibromatosis type 1 (NF1) is one of the most frequent hereditary diseases and is caused by mutations of the NF1 gene at 17q22.1. Despite a highly variable clinical expression, benign tumors of the peripheral nerve sheath, termed neurofibromas, are the hallmark feature of the disease. These tumors are characterized by a mixed cellular population which mainly consists of Schwann cells. Homozygous inactivation of the NF1 gene in Schwann cells is the key factor for neurofibroma development. However, it has been observed that neurofibromas frequently develop or progress during puberty or pregnancy. This suggests an additional hormonal influence on tumor growth in NF1.

Material and Methods: Schwann cells from NF1-associated neurofibromas were isolated and selectively expanded in vitro. Different forskolin-requirements of NF1 (±) and NF1 (–/–) cells enabled a genotype-specific selection of neurofibroma-derived Schwann cells. Different concentrations of progesterone were added and proliferation rates were determined by analyzing the BrdU incorporation rate. Indirect immunofluorescence staining was used to visualize progesterone receptors in these Schwann cells.

Results: We could show that NF Schwann cells express progesterone receptors and can be induced to proliferate by addition of progesterone. Our data indicate that the proliferative effect of progesterone on Schwann cells is more pronounced in the absence of neurofibromin.

Conclusions: Tumor growth in NF1 can be stimulated by progesterone and thus is – at least in part – hormone-dependent. This helps to explain many clinically well-documented observations and might have therapeutic implications in future.

Supported by Deutsche Krebshilfe (50–2713-Ro 1)