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  • Original Paper
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The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation

Abstract

Neuroblastoma (NB) is a childhood cancer that arises in the adrenal gland and often shows differentiated neuronal and glial elements. The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype. Thus, we hypothesized that the RET and TRKA signal pathways collaborate to instruct NB differentiation, reminiscent of normal neuronal maturation. Here, we demonstrate that activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increases expression of the RET receptor complex in a panel of malignant human NB cell lines, indicative of a positive feedback mechanism. GDNF also induces growth cessation concomitant with an arrest of cells in the G0/G1 phase of the cell cycle. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the NGF-mediated differentiation signal. Differentiated NB cells downregulate expression of the amplified N-myc gene, concurrent with the arrest of cell proliferation, while expressing neuron-specific markers (i.e., SCG10). Interestingly, maintenance of differentiated NB cells in culture is independent of the trophic activity of GDNF, but depends on TRKA signaling, thereby re-enacting the differentiation of normal sympathoadrenal (SA) progenitor cells.

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Abbreviations

ActD:

actinomycin D

CNTF:

ciliarly neurotrophic factor

DMEM:

Dulbecco's modified eagle's medium

GDNF:

glial cell line-derived neurotrophic factor

GFL:

GDNF family ligands

GFRα:

GDNF-family receptor-α

GPI:

glycosyl-phosphatidylinositol

IP:

immunoprecipitation

NGF:

nerve growth factor

NTN:

neurturin

PY:

phosphotyrosine

SA:

sympathoadrenal

References

  • Airaksinen MS and Saarma M . (2002). Nat. Rev. Neurosci., 3, 383–394.

  • Anderson DJ, Groves A, Lo L, Ma Q, Rao M, Shah NM and Sommer L . (1997). Cold Spring Harb. Symp. Quant. Biol., 62, 493–504.

  • Baldassarre G, Bruni P, Boccia A, Salvatore G, Melillo RM, Motti ML, Napolitano M, Belletti B, Fusco A, Santoro M and Viglietto G . (2002). Oncogene, 21, 1739–1749.

  • Barnett MW, Fisher CE, Perona-Wright G and Davies JA . (2002). J. Cell Sci., 115, 4495–4503.

  • Barone MV, Sepe L, Melillo RM, Mineo A, Santelli G, Monaco C, Castellone MD, Tramontano D, Fusco A and Santoro M . (2001). Oncogene, 20, 6973–6982.

  • Barrett GL . (2000). Prog. Neurobiol., 61, 205–229.

  • Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM, Bresnahan JC, Hempstead BL and Yoon SO . (2002). Neuron, 36, 375–386.

  • Berwanger B, Hartmann O, Bergmann E, Bernard S, Nielsen D, Krause M, Kartal A, Flynn D, Wiedemeyer R, Schwab M, Schafer H, Christiansen H and Eilers M . (2002). Cancer Cell, 2, 377–386.

  • Biedler JL and Spengler BA . (1976). Science, 191, 185–187.

  • Bogenmann E . (1996). Int. J. Cancer, 67, 379–385.

  • Bogenmann E, Peterson S, Maekawa K and Matsushima H . (1998). Oncogene, 17, 2367–2376.

  • Bothwell M . (1995). Annu. Rev. Neruosci., 18, 223–253.

  • Brodeur GM . (2003). Nat. Rev. Cancer, 3, 203–216.

  • Bunone G, Borrello MG, Picetti R, Bongarzone I, Peverali FA, de Franciscis V, Della Valle G and Pierotti MA . (1995). Exp. Cell Res., 217, 92–99.

  • Cosgaya JM, Chan JR and Shooter EM . (2002). Science, 298, 1245–1248.

  • Creedon DJ, Tansey MG, Baloh RH, Osborne PA, Lampe PA, Fahrner TJ, Heuckeroth RO, Milbrandt J and Johnson Jr EM . (1997). Proc. Natl. Acad. Sci. USA, 94, 7018–7023.

  • Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts Meek S, Armanini MP, Ling LH, MacMahon SB, Shelton DL, Levinson AD and X . (1994). Cell, 76, 1001–1011.

  • Dechant G and Barde YA . (2002). Nat. Neurosci., 5, 1131–1136.

  • Encinas M, Tansey MG, Tsui-Pierchala BA, Comella JX, Milbrandt J and Johnson Jr EM . (2001). J. Neurosci., 21, 1464–1472.

  • Fukuda T, Kiuchi K and Takahashi M . (2002). J. Biol. Chem., 277, 19114–19121.

  • Goodfellow PJ . (1994). Curr. Opin. Genet. Dev., 4, 446–452.

  • Hempstead BL . (2002). Curr. Opin. Neurobiol., 12, 260–267.

  • Hishiki T, Nimura Y, Isogai E, Kondo K, Ichimiya S, Nakamura Y, Ozaki T, Sakiyama S, Hirose M, Seki N, Takahashi H, Ohnuma N, Tanabe M and Nakagawara A . (1998). Cancer Res., 58, 2158–2165.

  • Hofstra RM, Cheng NC, Hansen C, Stulp RP, Stelwagen T, Clausen N, Tommerup N, Caron H, Westerveld A, Versteeg R and Buys CH . (1996). Hum. Genet, 97, 362–364.

  • Huang EJ and Reichardt LF . (2001). Annu. Rev. Neurosci., 24, 677–736.

  • Ip NY and Yancopoulos GD . (1996). Annu. Rev. Neurosci., 19, 491–515.

  • Krieglstein K, Henheik P, Farkas L, Jaszai J, Galter D, Krohn K and Unsicker K . (1998). J. Neurosci., 18, 9822–9834.

  • Kumar S, Steward JK, Waghe M, Pearson D, Edwards DC, Fenton EL and Griffith AH . (1970). J. Pediatr. Surg., 5, 18–22.

  • Lee FS, Kim AH, Khursigara G and Chao MV . (2001). Curr. Opin. Neurobiol., 11, 281–286.

  • Manie S, Santoro M, Fusco A and Billaud M . (2001). Trends Genet., 17, 580–589.

  • Matsushima H and Bogenmann E . (1992a). Int. J. Cancer, 51, 250–258.

  • Matsushima H and Bogenmann E . (1992b). Int. J. Cancer, 51, 727–732.

  • Matsushima H and Bogenmann E . (1993a). Mol. Cell. Biol., 13, 7447–7456.

  • Matsushima H and Bogenmann E . (1993b). Advances in Neuroblastoma Research 4 Evans A (ed.). John Wiley and Sons, Inc.: New York.

    Google Scholar 

  • Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB and Reynolds CP . (1999). N. Engl. J. Med., 341, 1165–1173.

  • Miyake M, Suzuki T, Shimada H, Stram D and Seeger RC . (1994). Prog. Clin. Biol. Res., 385, 163–168.

  • Molliver DC and Snider WD . (1997). J. Comp. Neurol., 381, 428–438.

  • Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver Moore K and Rosenthal A . (1996). Nature, 382, 76–79.

  • Nakagawara A, Arima Nakagawara M, Scavarda NJ, Azar CG, Cantor AB and Brodeur GM . (1993). N. Engl. J. Med., 328, 847–854.

  • Nakamura T, Ishizaka Y, Nagao M, Hara M and Ishikawa T . (1994). J. Pathol., 172, 255–260.

  • Natarajan D, Marcos-Gutierrez C, Pachnis V and de Graaff E . (2002). Development, 129, 5151–5160.

  • Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H and Westphal H . (1996). Nature, 382, 73–76.

  • Roux PP and Barker PA . (2002). Prog. Neurobiol., 67, 203–233.

  • Santoro M, Rosati R, Grieco M, Berlingieri MT, D’Amato GL, De Franciscis V and Fusco A . (1990). Oncogene, 5, 1595–1598.

  • Seeger RC and Reynolds CP . (1993). Cancer Med. Holland JF, Frei III E, Bast RC, Kufe DW, Morton DL and Weichselbaum RR (eds). Lea & Febiger: Philadelphia, pp 2172–2184.

    Google Scholar 

  • Shimada H, Chatten J, Newton Jr W, Sachs N, Hamoudi AB, Chiba T, Marsden HB and Misugi K . (1984). J. Natl. Cancer Inst., 73, 405–416.

  • Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ . (2000). Pharm. Acta Helv., 74, 265–272.

  • Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A, Lira SA and Barbacid M . (1994). Nature, 368, 246–249.

  • Stein R, Orit S and Anderson DJ . (1988). Dev. Biol., 127, 316–325.

  • Takahashi M . (2001). Cytokine Growth Factor Rev., 12, 361–373.

  • Thiele CJ, Reynolds CP and Israel MA . (1985). Nature, 313, 404–406.

  • Torres M and Bogenmann E . (1996). Oncogene, 12, 77–86.

  • Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE and Rosenthal A . (1996). Nature, 382, 80–83.

  • Tsui-Pierchala BA, Milbrandt J and Johnson Jr EM . (2002). Neuron, 33, 261–273.

  • Wang KC, Kim JA, Sivasankaran R, Segal R and He Z . (2002). Nature, 420, 74–78.

  • Westermann F and Schwab M . (2002). Cancer Lett., 184, 127–147.

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Acknowledgements

This work was supported by a grant from the NIH (RO1 NS36978).

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Correspondence to Emil Bogenmann.

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Peterson, S., Bogenmann, E. The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Oncogene 23, 213–225 (2004). https://doi.org/10.1038/sj.onc.1206980

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