Abstract
Background
Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited disorder that affects both the skin and the nervous system. NF1 occurs due to the mutations in the NF1 gene. Neurofibromas are the most common Schwann cell-based tumors in NF1 patients, which are mainly categorized into dermal and plexiform neurofibromas. Studies on different tumor types demonstrate that CXCR4 expression increases in tumor tissues and is linked to metastasis and cancer progression.
Purpose
In the present study, we aimed to analyze the gene expression of CXCR4, and its ligand CXCL12, in human neurofibromas.
Methods
Eight NF1 patients aged between 5 and 37 (2 males, 6 females) were selected. The patient group comprised 1 plexiform neurofibroma, 1 pheochromocytoma, and 6 dermal neurofibromas. Following pathological examination and diagnosis, tumors were co-stained with antibodies against Schwann cell marker S100 and target molecule CXCR4. CXCR4 expression in Schwann cell-based tumors was detected at the protein level. RNA isolated from the same tumors was used for RT-PCR-based studies to measure the quantitative expression of CXCR4 and CXCL12.
Results
CXCR4 gene expression increased 3- to 120-fold and CXCL12 gene expression increased 33- to 512-fold in all human Schwann cell-based tumors.
Conclusion
In order to validate the role of CXCR4 and its relationship with CXCL12 in NF1, future studies should be performed with additional tumors and different tumor types.
Similar content being viewed by others
References
Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL (2009) Neurofibromatosis type 1 revisited. Pediatrics 123:124–133
Boyd KP, Korf BR, Theos A (2009) Neurofibromatosis type 1. J Am Acad Dermatol 61:1–16
Feldkamp MM, Angelov L, Guha A (1999) Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway. Surg Neurol 51:211–218
Carroll SL (2011) Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms. Acta Neuropathol 123:321–348
Staser K, Yang FC, Clapp DW (2010) Mast cells and the neurofibroma microenvironment. Blood 116:157–164
Cichowski K, Jacks T (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604
Kolberg M, Høland M, Agesen TH, Brekke HR, Liestøl K, Hall KS, Mertens F, Picci P, Smeland S, Lothe RA (2013) Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncology 15:135–147
Kuil J, Buckle T, van Leeuwen FWB (2012) Imaging agents for the chemokine receptor 4 (CXCR4). Chem Soc Rev 41:5239–5261
Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599
Mo W, Chen J, Patel A, Zhang L, Chau V, Li Y, Cho W, Lim K, Xu J, Lazar AJ, Creigton CJ, Bolshakov S, McKay RM, Lev D, Le LQ, Parada LF (2013) CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152:1077–1090
Burger JA, Kipps TJ (2006) CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 107:1761–1767
Tseng D, Vasquez-Medrano DA, Brown JM (2011) Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br J Cancer 104:1805–1809
Singh AK, Arya RK, Trivedi AK, Sanyal S, Baral R, Dormond O, Briscoe DM, Datta D (2012) Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. Cytokine Growth Factor and Reviews 24:41–49
Domanska UM, Timmer-Bosscha H, Nagengast WB, Munnink THO, Kruizinga RC, Ananias HJK, Kliphuis NM, Huls G, De Vries EG, de Jong IJ, Walenkamp AM (2012) CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia 14:709–718
Le LQ, Shipman T, Burns DK, Parada LF (2009) Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4:453–463
Thomas L, Spurlock G, Eudall C, Thomas NS, Most M, Hamby SE, Chuzhanova N, Brems H, Legius E, Cooper DN, Upadhyaya M (2012) Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas. Eur J Hum Genet 20:411–419
Wang L, Chen W, Gao L, Yang Q, Liu B, Wu Z, Wang Y, Sun Y (2012) High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World Journal of Surgical Oncology 10:212–219
Zhang M, Liu H, Teng X, Wang H, Cui J, Jia SS, Gu XY, Li ZG (2012) The differences in CXCR4 protein expression are significant for the five molecular subtypes of breast cancer. Ultrastruct Pathol 36:381–386
Gagliardi F, Narayanan A, Reni M, Franzin A, Mazza E, Boari N, Balio M, Zordan P, Mortini P (2014) The role of CXCR4 in highly malignant human gliomas biology: current knowledge and future directions. Glia 62:1015–1023
Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim AR, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC (2016) Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N Engl J Med 375:2550–2560
Hirbe AC, Gutmann DH (2014) Neurofibromatosis type 1: a multidisciplinary approach to care. The Lancet Neurology 13:834–843
Acknowledgments
The authors would like to thank all families who participated in this work.
Funding
This study was supported by the Hacettepe University Scientific Research Foundation (06 01 101 021).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Karaosmanoglu, B., Kocaefe, Ç.Y., Söylemezoğlu, F. et al. Heightened CXCR4 and CXCL12 expression in NF1-associated neurofibromas. Childs Nerv Syst 34, 877–882 (2018). https://doi.org/10.1007/s00381-018-3745-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00381-018-3745-6