The effect of estradiol, testosterone, and human chorionic gonadotropin on the proliferation of Schwann cells with NF1 +/− or NF1 −/− genotype derived from human cutaneous neurofibromas
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Dermal neurofibromas are the hallmarks of neurofibromatosis type 1 (NF1). Neurofibromas harbor Schwann cells with two different genotypes: Schwann cells which carry the germline mutation and a healthy NF1 allele (NF1 +/−), and a subpopulation of Schwann cells which harbor the so-called second hit leading to inactivation of both NF1 alleles (NF1 −/−). The second hit in the NF1 gene of Schwann cells is considered to be the initial step in the development of neurofibromas. Dermal neurofibromas typically start to grow in puberty, and their number and size increase during pregnancy, indicating hormone responsiveness. This is the first study to address the effect of human chorionic gonadotropin (hCG) on the proliferation of human NF1 +/− and NF1 −/− Schwann cells in vitro. In addition, the effects of estradiol and testosterone were also investigated. The results showed that NF1 −/− Schwann cells were more sensitive to estradiol, testosterone, and human chorionic gonadotropin than NF1 +/− cells. Specifically, the proliferation of NF1 −/− Schwann cells was increased by up to 99, 110, and 170% compared to vehicle control when treated with estradiol, testosterone, and hCG, respectively. Interestingly, no effect of estradiol, testosterone, or hCG on the proliferation of the cells with NF1 +/− genotype was observed. To conclude, the somatic second hit in the NF1 gene sensitizes Schwann cells to sex hormones resulting in a highly increased proliferation. Our results highlight the significance of sex hormones in the regulation of neurofibroma growth.
KeywordsNeurofibromatosis 1 Schwann cell Sex hormone Estradiol Testosterone Human chorionic gonadotropin
Neurofibromatosis type 1
Human NF1 gene
Cells carrying the constitutional NF1 mutation only
Cells with the NF1 second hit
National Institutes of Health
Malignant peripheral nerve sheath tumor
Human chorionic gonadotropin
Fetal bovine serum
We would like to thank Mr. Miso Immonen for technical support. This work was supported by The Turku University Foundation and The Jalmari and Rauha Ahokas Foundation.
Raw data is available on request.
JP conceived the study. JP and SP made a significant contribution to writing the paper. SP collected the neurofibroma samples. RAK analyzed the data, drafted, and revised the paper. PP designed the experiments, cultured Schwann cells, performed the assays, analyzed the data, and wrote the paper. All authors read and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
This study has been performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Southwest Finland Hospital District, and patients gave their informed written consents. The study was carried out at Turku University Hospital and the University of Turku.
- 4.Riccardi VM (1992) Neurofibromatosis: phenotype, natural history and pathogenesis. The John Hopkins University Press, Baltimore, pp 1–85Google Scholar
- 19.Siriphorn A, Chompoopong S, Floyd CL (2010) 17β-estradiol protects Schwann cells against H2O2-induced cytotoxicity and increases transplanted Schwann cell survival in a cervical hemicontusion spinal cord injury model. J Neurochem 115:864–872. https://doi.org/10.1111/j.1471-4159.2010.06770.x CrossRefPubMedGoogle Scholar
- 20.Chen Y, Guo W, Xu L, Li W, Cheng M, Hu Y, Xu W (2016) 17β-Estradiol promotes schwann cell proliferation and differentiation, accelerating early remyelination in a mouse peripheral nerve injury model. Biomed Res Int 2016:7891202 https://doi.org/10.1155/2016/7891202 PubMedPubMedCentralCrossRefGoogle Scholar
- 21.Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, Riccardi VM, Pukkala E, Pitkäniemi J, Peltonen S, Peltonen J (2016) Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol. https://doi.org/10.1200/JCO.2015.65.3576 PubMedCrossRefGoogle Scholar
- 23.Perrin GQ, Li H, Fishbein L, Thomson SA, Hwang MS, Scarborough MT, Yachnis AT, Wallace MR, Mareci TH, Muir D (2007) An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation. Lab Invest 87:1092–1102. https://doi.org/10.1038/labinvest.3700675 CrossRefPubMedGoogle Scholar
- 28.Maertens O, Brems H, Vandesompele J, De Raedt T, Heyns I, Rosenbaum T, De Schepper S, De Paepe A, Mortier G, Janssens S, Speleman F, Legius E, Messiaen L (2006) Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat 27:1030–1040. https://doi.org/10.1002/humu.20389 CrossRefPubMedGoogle Scholar
- 29.Stumpf DA, Alksne JF, Annegers JF, Brown SS, Conneally PM, Housman D, Leppert MF, Miller JP, Moss ML, Pileggi AJ, Rapin I, Strohman RC, Swanson LW, Zimmerman A (1988) Neurofibromatosis conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 45:575–578CrossRefGoogle Scholar
- 32.Liao RS, Ma S, Miao L, Li R, Yin Y, Raj GV (2013) Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Transl Androl Urol 2:187–196. https://doi.org/10.3978/j.issn.2223-4683.2013.09.07 PubMedPubMedCentralCrossRefGoogle Scholar
- 33.Fan HY, Shimada M, Liu Z, Cahill N, Noma N, Wu Y, Gossen J, Richards JS (2008) Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation. Development 135:2127–2137. https://doi.org/10.1242/dev.020560 CrossRefPubMedPubMedCentralGoogle Scholar