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. 2006 Apr 5;15(1):17–22. doi: 10.1111/j.1750-3639.2005.tb00095.x

Reduced Apoptosis Rates in Human Schwannomas

Tamara Utermark 1,*,✉, Katherine Kaempchen 1,*, Gregor Antoniadis 2, C Oliver Hanemann 1
PMCID: PMC8095751  PMID: 15779232

Abstract

Schwannomas, tumors originating from Schwann cells, represent a frequent neurological tumor and can occur both in a genetic disorder called neurofibromatosis type 2 (NF2) and sporadically. In both cases the genetic background is identical as all schwannomas are caused by biallelic mutations in the tumor suppressor gene NF2 coding for merlin. Mutations in this gene have also been found to be responsible for 50% to 60% of spontaneous and 100% of the NF2 associated meningiomas. The NF2 gene product, merlin, links transmembrane proteins to the cytoskeleton and is involved in intracellular signaling processes. It has previously been shown that reexpression of wild‐type merlin in primary human schwannoma cells leads to an increase in the number of apoptotic cells. Here, we report in vivo and in vitro evidence that the basal apoptosis rate of primary human schwannoma cells is reduced in comparison to that of normal Schwann cells, supporting the idea that in this benign tumor type, apoptosis has a role in tumorigenesis.

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REFERENCES

  • 1. . (1994) National Institutes of Health Consensus Development Conference Statement on Acoustic Neuroma , December 1113, 1991. The Consensus Development Panel. Arch Neurol 51:201–207. [DOI] [PubMed] [Google Scholar]
  • 2. Abend M (2003) Reasons to reconsider the significance of apoptosis for cancer therapy. Int J Radiat Biol 79:927–941. [DOI] [PubMed] [Google Scholar]
  • 3. Bijisma EK, Brouwer‐Mladin R, Bosch DA, Sterveld A, Hulsebos TJM (1992) Molecular characterization of chromosome 22 deletions in schwannomas. Genes Chromosomes Cancer 5:201–205. [DOI] [PubMed] [Google Scholar]
  • 4. Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G (2003) Disruption of ErbB receptor signaling in adult non‐myelinating Schwann cells causes progressive sensory loss. Nat Neurosci 6:1186–1193. [DOI] [PubMed] [Google Scholar]
  • 5. Cheng HL, Steinway ML, Xin X, Feldman EL (2001) Insulin‐like growth factor‐I and Bcl‐X(L) inhibit c‐jun N‐terminal kinase activation and rescue Schwann cells from apoptosis. J Neurochem 76:935–943. [DOI] [PubMed] [Google Scholar]
  • 6. Dowsing BJ, Morrison WA, Nicola NA, Starkey GP, Bucci T, Kilpatrick TJ (1999) Leukemia inhibitory factor is an autocrine survival factor for Schwann cells. J Neurochem 73:96–104. [DOI] [PubMed] [Google Scholar]
  • 7. Fawcett JW, Keynes RJ (1990) Peripheral nerve regeneration. Annu RevNeurosci 13:43–60. [DOI] [PubMed] [Google Scholar]
  • 8. Grinspan JB, Marchionni MA, Reeves M, Cou‐laloglou M, Scherer SS (1996) Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J Neurosci 16:6107–6118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Hagel C, Lindenau M, Lamszus K, Kluwe L, Stavrou D, Mautner VF (2002) Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens. Acta Neuropathol (Berl) 104:179–187. [DOI] [PubMed] [Google Scholar]
  • 10. Hanemann CO, Rosenbaum C, Kupfer S, Wosch S, Stoegbauer F, Mueller HW (1998) Improved culture methods to expand Schwann cells with altered growth behaviour from CMT1A patients. GLIA 23:89–98. [DOI] [PubMed] [Google Scholar]
  • 11. Hochedlinger K, Wagner EF, Sabapathy K (2002) Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis. Oncogene 21:2441–2445. [DOI] [PubMed] [Google Scholar]
  • 12. Kaempchen K, Mielke K, Utermark T, Lang‐messer S, Hanemann CO (2003) Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Hum Mol Genetics 12:1211–1221. [DOI] [PubMed] [Google Scholar]
  • 13. Kimura Y, Saya H, Nakao M (2000) Calpain‐dependent proteolysis of NF2 protein: involvement in schwannomas and meningiomas. Neuropathology 20:153–160. [DOI] [PubMed] [Google Scholar]
  • 14. Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667–676. [DOI] [PubMed] [Google Scholar]
  • 15. Lin A, Dibling B (2002) The true face of JNK activation in apoptosis. Aging Cell 1:112–116. [DOI] [PubMed] [Google Scholar]
  • 16. Meier C, Parmantier E, Brennan A, Mirsky R, Jessen KR (1999) Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin‐like growth factor, neurotrophin‐3, and platelet‐derived growth factor‐BB. J Neurosci 19:3847–3859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Mendenhall WM, Friedman WA, Amdur RJ, Antonelli PJ (2004) Management of acoustic schwannoma. Am J Otolaryngol 25:38–47. [DOI] [PubMed] [Google Scholar]
  • 18. Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H, Herrlich P (2001) The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 15:968–980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Pelton PD, Sherman LS, Rizvi TA, Marchionni MA, Wood P, Friedman RA, Ratner N (1998) Ruffling membrane, stress fiber, cell spreading and proliferation abnormalities in human Schwannoma cells. Oncogene 17:2195–2209. [DOI] [PubMed] [Google Scholar]
  • 20. Petratos S, Butzkueven H, Shipham K, Cooper H, Bucci T, Reid K, Lopes E, Emery B, Cheema SS, Kilpatrick TJ (2003) Schwann cell apoptosis in the postnatal axotomized sciatic nerve is mediated via NGF through the low‐affinity neurotrophin receptor. J Neuropathol Exp Neurol 62:398–411. [DOI] [PubMed] [Google Scholar]
  • 21. Rosenbaum C, Kluwe L, Mautner VF, Friedrich RE, Mueller HW, Hanemann CO (1998) Isolation and characterization of Schwann cells from neurofibromatosis type 2 patients. Neurobiol Dis 5:55–64. [DOI] [PubMed] [Google Scholar]
  • 22. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang‐Xuan K, Demczuk S, Desmaze C, Plougastel B (1993) Alteration in a new gene encoding a putative membrane‐organizing protein causes neuro‐fibromatosis type 2 (see comments). Nature 363:515–521. [DOI] [PubMed] [Google Scholar]
  • 23. Rowe JG, Radatz MW, Walton L, Hampshire A, Seaman S, Kemeny AA (2003) Gamma knife stereotactic radiosurgery for unilateral acoustic neuromas. J Neurol Neurosurg Psychiatry 74:1536–1542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Sainio M, Zhao F, Heiska L, Turunen O, den Bakker M, Zwarthoff E, Lutchman M, Rouleau GA, Jaaskelainen J, Vaheri A, Carpen O (1997) Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin‐containing cytoskeleton. J Cell Sci 110 (Pt 18):2249–2260. [DOI] [PubMed] [Google Scholar]
  • 25. Sainz J, Huynh DP, Figueroa K, Ragge NK, Baser ME, Pulst SM (1994) Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas. Hum Mol Genetics 3:885–891. [DOI] [PubMed] [Google Scholar]
  • 26. Schulze KM, Hanemann CO, Muller HW, Hanenberg H (2002) Transduction of wild‐type merlin into human schwannoma cells decreases schwannoma cell growth and induces apoptosis. Hum Mol Genetics 11:69–76. [DOI] [PubMed] [Google Scholar]
  • 27. Sherman L, Jacoby LB, Lampe J, Pelton P, Aguzzi A, Herrlich P, Ponta H (1997) CD44 expression is aberrant in benign Schwann cell tumors possessing mutations in the neurofibromatosis type 2, but not type 1, gene. Cancer Res 57:4889–4897. [PubMed] [Google Scholar]
  • 28. Sherman LS, Rizvi TA, Karyala S, Ratner N (2000) CD44 enhances neuregulin signaling by Schwann cells. J Cell Biol 150:1071–1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Sperfeld AD, Hein C, Schroder JM, Ludolph AC, Hanemann CO (2002) Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. Brain 125:996–1004. [DOI] [PubMed] [Google Scholar]
  • 30. Syroid DE, Maycox PR, Burrola PG, Liu N, Wen D, Lee KF, Lemke G, Kilpatrick TJ (1996) Cell death in the Schwann cell lineage and its regulation by neuregulin. Proc Natl Acad Sci U S A 93:9229–9234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Syroid DE, Zorick TS, Arbet‐Engels C, Kilpatrick TJ, Eckhart W, Lemke G (1999) A role for insulinlike growth factor‐I in the regulation of Schwann cell survival. J Neurosci 19:2059–2068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Takeuchi K, Sato N, Kasahara H, Funayama N, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1994) Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members. J Cell Biol 125:1371–1384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Trachtenberg JT, Thompson WJ (1996) Schwann cell apoptosis at developing neuromuscular junctions is regulated by glial growth factor. Nature 379:174–177. [DOI] [PubMed] [Google Scholar]
  • 34. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K (1993) A novel moesin‐, ezrin‐, radixin‐like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 75:826‐. [DOI] [PubMed] [Google Scholar]
  • 35. Utermark T, Kaempchen K, Hanemann CO (2003) Pathological adhesion of primary human schwannoma cells is dependent on altered expression of integrins. Brain Pathol 13:352–363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Wisdom R, Johnson RS, Moore C (1999) c‐Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBOJ 18:188–197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Wolff RK, Frazer KA, Jackler RK, Lanser MJ, Pitts LH, Cox DR (1992) Analysis of chromosome 22 deletions in neurofibromatosis type 2‐related tumors. Am J Hum Genetics 51:478–485. [PMC free article] [PubMed] [Google Scholar]

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