Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Sep 23

PMID 36139671

Authors

Ling-Ling Ge

Ming-Yan Xing

Hai-Bing Zhang

Zhi-Chao Wang

Affiliations

Soon will be listed here.

Abstract

Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes.

Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas.

Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

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References

Jessen K, Mirsky R . The repair Schwann cell and its function in regenerating nerves. J Physiol. 2016; 594(13):3521-31. PMC: 4929314. DOI: 10.1113/JP270874. View

Uusitalo E, Rantanen M, Kallionpaa R, Poyhonen M, Leppavirta J, Yla-Outinen H . Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. J Clin Oncol. 2016; 34(17):1978-86. DOI: 10.1200/JCO.2015.65.3576. View

Menon A, Anderson K, Riccardi V, Chung R, Whaley J, Yandell D . Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A. 1990; 87(14):5435-9. PMC: 54339. DOI: 10.1073/pnas.87.14.5435. View

Faulkner S, Jobling P, March B, Jiang C, Hondermarck H . Tumor Neurobiology and the War of Nerves in Cancer. Cancer Discov. 2019; 9(6):702-710. DOI: 10.1158/2159-8290.CD-18-1398. View

Keng V, Rahrmann E, Watson A, Tschida B, Moertel C, Jessen W . PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res. 2012; 72(13):3405-13. PMC: 3428071. DOI: 10.1158/0008-5472.CAN-11-4092. View

Evans D, Baser M, McGaughran J, Sharif S, Howard E, Moran A . Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002; 39(5):311-4. PMC: 1735122. DOI: 10.1136/jmg.39.5.311. View

Brosseau J, Sathe A, Wang Y, Nguyen T, Glass 2nd D, Xing C . Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing. Acta Neuropathol Commun. 2021; 9(1):11. PMC: 7792184. DOI: 10.1186/s40478-020-01103-4. View

Le L, Liu C, Shipman T, Chen Z, Suter U, Parada L . Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res. 2011; 71(13):4686-95. PMC: 3145496. DOI: 10.1158/0008-5472.CAN-10-4577. View

Soto J, Ding X, Wang A, Li S . Neural crest-like stem cells for tissue regeneration. Stem Cells Transl Med. 2021; 10(5):681-693. PMC: 8046096. DOI: 10.1002/sctm.20-0361. View

10.

Zahalka A, Frenette P . Nerves in cancer. Nat Rev Cancer. 2020; 20(3):143-157. PMC: 7709871. DOI: 10.1038/s41568-019-0237-2. View

11.

Chaney K, Perrino M, Kershner L, Patel A, Wu J, Choi K . Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST. Cancer Res. 2020; 80(21):4720-4730. PMC: 7968129. DOI: 10.1158/0008-5472.CAN-19-1429. View

12.

Saito H, Yoshida T, Yamazaki H, Suzuki N . Conditional N-rasG12V expression promotes manifestations of neurofibromatosis in a mouse model. Oncogene. 2007; 26(32):4714-9. DOI: 10.1038/sj.onc.1210250. View

13.

Jessen K, Mirsky R . Schwann cells and their precursors emerge as major regulators of nerve development. Trends Neurosci. 1999; 22(9):402-10. DOI: 10.1016/s0166-2236(98)01391-5. View

14.

Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns D . Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation. Cancer Cell. 2008; 13(2):117-28. DOI: 10.1016/j.ccr.2008.01.002. View

15.

Eckert J, Byer S, Clodfelder-Miller B, Carroll S . Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells. Glia. 2009; 57(14):1501-20. PMC: 2744852. DOI: 10.1002/glia.20866. View

16.

Woodruff J . Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis. Am J Med Genet. 1999; 89(1):23-30. DOI: 10.1002/(sici)1096-8628(19990326)89:1<23::aid-ajmg6>3.0.co;2-#. View

17.

Chen Z, Liu C, Patel A, Liao C, Wang Y, Le L . Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell. 2014; 26(5):695-706. PMC: 4254535. DOI: 10.1016/j.ccell.2014.09.009. View

18.

Mayes D, Rizvi T, Cancelas J, Kolasinski N, Ciraolo G, Stemmer-Rachamimov A . Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res. 2011; 71(13):4675-85. PMC: 3464476. DOI: 10.1158/0008-5472.CAN-10-4558. View

19.

Shamash S, Reichert F, Rotshenker S . The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci. 2002; 22(8):3052-60. PMC: 6757534. DOI: 20026249. View

20.

Zhu Y, Ghosh P, Charnay P, Burns D, Parada L . Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science. 2002; 296(5569):920-2. PMC: 3024710. DOI: 10.1126/science.1068452. View