Abstract
Patients with neurofibromatosis type 1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Although tumor suppressor gene mutations play an important role in MPNST pathogenesis, it is likely that dysregulated signaling by as yet unidentified growth factors also contributes to the formation of these sarcomas. To test the hypothesis that neuregulin-1 (NRG-1) growth factors promote mitogenesis in MPNSTs, we examined the expression and action of NRG-1 in human MPNSTs and neurofibromas, the benign precursor lesions from which MPNSTs arise. Multiple α and β transmembrane precursors from the class II and III NRG-1 subfamilies are present in both tumor types. Neoplastic Schwann cells within these neoplasms variably express the erbB kinases mediating NRG-1 responses (erbB2, erbB3 and/or erbB4). Human MPNST cell lines (Mash-1, YST-1, NMS-2 and NMS-2PC cells) similarly coexpress multiple NRG-1 isoforms and erbB receptors. These MPNST lines are NRG-1 responsive and demonstrate constitutive erbB phosphorylation. Treatment with PD168393 and PD158780, two structurally and mechanistically distinct erbB inhibitors, abolishes erbB phosphorylation and reduces DNA synthesis in these lines. These findings suggest that autocrine and/or paracrine NRG-1/erbB signaling promotes neoplastic Schwann cell proliferation and may be an important therapeutic target in neurofibromas and MPNSTs.
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References
Bao J, Wolpowitz D, Role LW and Talmage DA . (2003). J. Cell Biol., 161, 1133–1141.
Bargmann CI, Hung MC and Weinberg RA . (1986). Cell, 45, 649–657.
Bargmann CI and Weinberg RA . (1988). EMBO J., 7, 2043–2052.
Ben-Baruch N and Yarden Y . (1994). Proc. Soc. Exp. Biol. Med., 206, 221–227.
Birindelli S, Perrone F, Oggionni M, Lavarino C, Pasini B, Vergani B, Ranzani GN, Pierotti MA and Pilotti S . (2001). Lab. Invest., 81, 833–844.
Brockes JP, Breakefield XO and Martuza RL . (1986). Ann. Neurol., 20, 317–322.
Carpenter G . (2003). Exp. Cell Res., 284, 66–77.
Carroll SL, Miller ML, Frohnert PW, Kim SS and Corbett JA . (1997). J. Neurosci., 17, 1642–1659.
Carroll SL and Stonecypher MS . (2004). J. Neuropathol. Exp. Neurol., 63, 1115–1123.
Carroll SL and Stonecypher MS . (2005). J. Neuropathol. Exp. Neurol., 64, 1–9.
DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D and Ratner N . (2000). J. Clin. Invest., 105, 1233–1241.
Di Marco E, Pierce JH, Knicley CL and Di Fiore PP . (1990). Mol Cell Biol, 10, 3247–3252.
Dong Z, Brennan A, Liu N, Yarden Y, Lefkowitz G, Mirsky R and Jessen KR . (1995). Neuron, 15, 585–596.
Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM and Ilstrup DM . (1986). Cancer, 57, 2006–2021.
Endo H, Utani A and Shinkai H . (2002). Br. J. Dermatol., 147, 821–822.
Falls DL . (2003). Exp. Cell Res., 284, 14–30.
Ferner RE and Gutmann DH . (2002). Cancer Res., 62, 1573–1577.
Ferner RE and O'Doherty MJ . (2002). Curr. Opin. Neurol., 15, 679–684.
Frohnert PW, Stonecypher MS and Carroll SL . (2003a). Glia, 43, 104–118.
Frohnert PW, Stonecypher MS and Carroll SL . (2003b). J. Neuropathol. Exp. Neurol., 62, 520–529.
Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S and Dobrusin EM . (1998). Proc. Natl. Acad. Sci. USA, 95, 12022–12027.
Fry DW, Nelson JM, Slintak V, Keller PR, Rewcastle GW, Denny WA, Zhou H and Bridges AJ . (1997). Biochem. Pharmacol., 54, 877–887.
Gerecke KM, Wyss JM, Karavanova I, Buonanno A and Carroll SL . (2001). J. Comp. Neurol., 433, 86–100.
Graus-Porta D, Beerli RR, Daly JM and Hynes NE . (1997). EMBO J., 16, 1647–1655.
Gutmann DH . (2001). Hum. Mol. Genet., 10, 747–755.
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A and Viskochil D . (1997). JAMA, 278, 51–57.
Hudziak RM, Schlessinger J and Ullrich A . (1987). Proc. Natl. Acad. Sci. USA, 84, 7159–7163.
Huijbregts RPH, Roth KA, Schmidt RE and Carroll SL . (2003). J. Neurosci., 23, 7269–7280.
Imaizumi S, Motoyama T, Ogose A, Hotta T and Takahashi HE . (1998). Virchows Arch., 433, 435–441.
Kluwe L, Friedrich R and Mautner VF . (1999). Genes Chromosomes Cancer, 24, 283–285.
Kourea HP, Cordon-Cardo C, Dudas M, Leung D and Woodruff JM . (1999a). Am. J. Pathol., 155, 1885–1891.
Kourea HP, Orlow I, Scheithauer BW, Cordon-Cardo C and Woodruff JM . (1999b). Am. J. Pathol., 155, 1855–1860.
Lakkis MM and Tennekoon GI . (2000). J. Neurosci. Res., 62, 755–763.
Legius E, Dierick H, Wu R, Hall BK, Marynen P, Cassiman JJ and Glover TW . (1994). Genes Chromosomes Cancer, 10, 250–255.
Legius E, Marchuk DA, Collins FS and Glover TW . (1993). Nat. Genet., 3, 122–125.
Li H, Velasco-Miguel S, Vass WC, Parada LF and DeClue JE . (2002). Cancer Res., 62, 4507–4513.
Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP, Barker DF, Ledbetter DH, Kleider A, Martuza RL, Gusella JF and Seizinger BR . (1990). Proc. Natl. Acad. Sci. USA, 87, 5435–5439.
Metheny LJ, Cappione AJ and Skuse GR . (1995). J. Neuropathol. Exp. Neurol., 54, 753–760.
Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH and Nave KA . (2004). Science, 304, 700–703.
Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A and Pandiella A . (2000). Mol. Cell. Neurosci., 16, 631–648.
Morrissey TK, Levi ADO, Nuijens A, Sliwkowski MX and Bunge RP . (1995). Proc. Natl. Acad. Sci. USA, 92, 1431–1435.
Nagashima Y, Ohaki Y, Tanaka Y, Sumino K, Funabiki T, Okuyama T, Watanabe S, Umeda M and Misugi K . (1990). Virchows Archiv. B., 59, 321–327.
Nielsen GP, Stemmer-Rachamimov AO, Ino Y, Moller MB, Rosenberg AE and Louis DN . (1999). Am. J. Pathol., 155, 1879–1884.
Nikitin AY, Ballering LAP, Lyons J and Rajewsky MF . (1991). Proc. Natl. Acad. Sci. USA, 88, 9939–9943.
Parada LF . (2000). Biochim. Biophys. Acta, 1471, M13–M19.
Peles E and Yarden Y . (1993). BioEssays, 15, 815–824.
Perry A, Kunz SN, Fuller CE, Banerjee R, Marley EF, Liapis H, Watson MW and Gutmann DH . (2002). J. Neuropathol. Exp. Neurol., 61, 702–709.
Perry A, Roth KA, Banerjee R, Fuller CE and Gutmann DH . (2001). Am. J. Pathol., 159, 57–61.
Rahmatullah M, Schroering A, Rothblum K, Stahl RC, Urban B and Carey DJ . (1998). Mol. Cell. Biol., 18, 6245–6252.
Rutkowski JL, Wu K, Gutmann DH, Boyer PJ and Legius E . (2000). Hum. Mol. Genet., 9, 1059–1066.
Sherman L, Sleeman JP, Hennigan RF, Herrlich P and Ratner N . (1999). Oncogene, 18, 6692–6699.
Sherman LS, Atit R, Rosenbaum T, Cox AD and Ratner N . (2000). J. Biol. Chem., 275, 30740–30745.
Tucker T and Friedman JM . (2002). Clin. Genet., 62, 345–357.
Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ and Yarden Y . (1996). Mol. Cell. Biol., 16, 5276–5287.
Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ and Parada LF . (1999). Science, 286, 2176–2179.
Wakatsuki S, Kurisaki T and Sehara-Fujisawa A . (2004). J. Neurochem., 89, 119–123.
Wallace MR, Rasmussen SA, Lim IT, Bray BA, Zori RT and Muir D . (2000). Genes Chromosomes Cancer, 27, 117–123.
Weiner DB, Liu J, Cohen JA, Williams WV and Greene MI . (1989). Nature, 339, 230–231.
Wen D, Suggs SV, Karunagaran D, Liu N, Cupples RL, Luo Y, Janssen AM, Ben-Baruch N, Trollinger DB, Jacobsen VL, Meng S-Y, Lu HS, Hu S, Chang D, Yang W, Yanigahara D, Koski RA and Yarden Y . (1994). Mol. Cell. Biol., 14, 1909–1919.
Woodruff JM, Kourea HP, Louis DN and Scheithauer BW . (2000). Pathology and Genetics of Tumours of the Nervous System, First Edition. Kleihues P and Cavenee WK (ed). IARC Press: Lyon, pp. 172–174.
Yarden Y and Sliwkowski M . (2001). Nat. Rev. Mol. Cell Biol., 2, 127–137.
Zhu Y and Parada LF . (2001). Exp. Cell Res., 264, 19–28.
Acknowledgements
We thank Dr Kevin A Roth (Department of Pathology, UAB) for helpful comments on this manuscript. This work was supported by National Institute of Neurological Disorders and Stroke Grant R01 NS048353.
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Stonecypher, M., Byer, S., Grizzle, W. et al. Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors. Oncogene 24, 5589–5605 (2005). https://doi.org/10.1038/sj.onc.1208730
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DOI: https://doi.org/10.1038/sj.onc.1208730
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