TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-XL also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-XL also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB) 1The abbreviations used are: NB, neuroblastoma; NGF, nerve growth factor; MAPK, mitogen-activate protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; JNK, c-Jun NH2-terminal kinase; Z-VAD-fmk, benzyloxycarbonyl-VAD-fluoromethyl ketone; GFP, green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; KD, kinase-dead; Ptyr, phosphotyrosine; m.o.i., multiplicity of infection; PARP, poly(ADP-ribose) polymerase; tTA, tetracycline-responsive transcriptional activator. 1The abbreviations used are: NB, neuroblastoma; NGF, nerve growth factor; MAPK, mitogen-activate protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; JNK, c-Jun NH2-terminal kinase; Z-VAD-fmk, benzyloxycarbonyl-VAD-fluoromethyl ketone; GFP, green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; KD, kinase-dead; Ptyr, phosphotyrosine; m.o.i., multiplicity of infection; PARP, poly(ADP-ribose) polymerase; tTA, tetracycline-responsive transcriptional activator. is the most common solid extracranial solid tumor of childhood and likely arises from sympathoadrenal precursor cells. The median age at diagnosis is ∼18 months, and spontaneous tumor regression is frequently observed in patients diagnosed at 1 year of age or younger. In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1Aoyama M. Asai K. Shishikura T. Kawamoto T. Miyachi T. Yokoi T. Togari H. Wada Y. Kato T. Nakagawara A. Cancer Lett. 2001; 164: 51-60Crossref PubMed Scopus (77) Google Scholar, 2Hoehner J.C. Olsen L. Sandstedt B. Kaplan D.R. Pahlman S. Am. J. Pathol. 1995; 147: 102-113PubMed Google Scholar, 3Nakagawara A. Azar C.G. Scavarda N.J. Brodeur G.M. Mol. Cell. Biol. 1994; 14: 759-767Crossref PubMed Scopus (367) Google Scholar, 4Nakagawara A. Arima-Nakagawara M. Scavarda N.J. Azar C.G. Cantor A.B. Brodeur G.M. N. Engl. J. Med. 1993; 328: 847-854Crossref PubMed Scopus (604) Google Scholar). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5Kaplan D.R. Matsumoto K. Lucarelli E. Thiele C.J. Neuron. 1993; 11: 321-331Abstract Full Text PDF PubMed Scopus (311) Google Scholar, 6Jaboin J. Kim C.J. Kaplan D.R. Thiele C.J. Cancer Res. 2002; 62: 6756-6763PubMed Google Scholar, 7Ho R. Eggert A. Hishiki T. Minturn J.E. Ikegaki N. Foster P. Camoratto A.M. Evans A.E. Brodeur G.M. Cancer Res. 2002; 62: 6462-6466PubMed Google Scholar, 8Matsumoto K. Wada R.K. Yamashiro J.M. Kaplan D.R. Thiele C.J. Cancer Res. 1995; 55: 1798-1806PubMed Google Scholar, 9Middlemas D.S. Kihl B.K. Zhou J. Zhu X. J. Biol. Chem. 1999; 274: 16451-16460Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 10Scala S. Wosikowski K. Giannakakou P. Valle P. Biedler J.L. Spengler B.A. Lucarelli E. Bates S.E. Thiele C.J. Cancer Res. 1996; 56: 3737-3742PubMed Google Scholar), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11Chen J. Chattopadhyay B. Venkatakrishnan G. Ross A.H. Cell Growth & Differ. 1990; 1: 79-85PubMed Google Scholar, 12Matsushima H. Bogenmann E. Mol. Cell. Biol. 1993; 13: 7447-7456Crossref PubMed Scopus (88) Google Scholar, 13Lavenius E. Gestblom C. Johansson I. Nanberg E. Pahlman S. Cell Growth & Differ. 1995; 6: 727-736PubMed Google Scholar). This is consistent with TrkA being expressed in tumors that spontaneously regress. Most NB cell lines, which are derived from malignant tumors, lack or have very low levels of TrkA protein expression. Cell lines with low TrkA expression respond to NGF by differentiating into neuronal-like cells (11Chen J. Chattopadhyay B. Venkatakrishnan G. Ross A.H. Cell Growth & Differ. 1990; 1: 79-85PubMed Google Scholar). Similarly, expression of TrkA by transfection converts NGF non-responsive NB cells into NGF-responsive cells, both in culture and in vivo, with the typical responses being the cessation of cell growth and differentiation into neural and Schwann cells (12Matsushima H. Bogenmann E. Mol. Cell. Biol. 1993; 13: 7447-7456Crossref PubMed Scopus (88) Google Scholar). Thus, TrkA converts malignant NB cells into quiescent differentiated cells. An alternative or additional explanation for why TrkA is a good prognosis marker for NB that might contribute to spontaneous tumor regression is that it may induce apoptosis. Paradoxically, TrkA is a potent pro-survival protein for sympathetic and sensory neurons (14Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1653) Google Scholar), whereas it has been shown to induce, when overexpressed, the apoptosis of medulloblastoma cells (15Muragaki Y. Chou T.T. Kaplan D.R. Trojanowski J.Q. Lee V.M. J. Neurosci. 1997; 17: 530-542Crossref PubMed Google Scholar). In the following study, we asked whether expression of full-length TrkA (human TrkAI) would induce the apoptosis of NB cells. We find that TrkA, expressed at levels similar to that found in neurons, caused the apoptosis of NB cells with MYCN amplification while stimulating the survival of non-transformed sympathetic neurons. Apoptosis by TrkA was accompanied by alterations in the levels and/or the activities of a number of proteins involved in apoptotic signaling, including p53, Bcl-2, and caspase-3. We show that wild-type p53 expression and activity, and not p38 MAPK or p42/44 MAPK activities, were required to mediate TrkA-induced cell death. Our findings suggest that high expression of TrkA that occurs in good prognosis NB tumors may result in apoptosis and that this event is mediated by p53, which is wild-type in most NB tumors. Cell Culture—MYCN amplified human neuroblastoma Lan-1-15N (15N) cells (16Ciccarone V. Spengler B.A. Meyers M.B. Biedler J.L. Ross R.A. Cancer Res. 1989; 49: 219-225PubMed Google Scholar), NGP (17Brodeur G.M. Sekhon G. Goldstein M.N. Cancer. 1977; 40: 2256-2263Crossref PubMed Scopus (294) Google Scholar) cells, and p53 mutated SK-N-BE(2) NB cells (18Barnes E.N. Biedler J.L. Spengler B.A. Lyser K.M. In Vitro. 1981; 17: 619-631Crossref PubMed Scopus (39) Google Scholar) were cultured as described (5Kaplan D.R. Matsumoto K. Lucarelli E. Thiele C.J. Neuron. 1993; 11: 321-331Abstract Full Text PDF PubMed Scopus (311) Google Scholar). Primary sympathetic neurons were isolated and cultured as described previously (19Atwal J.K. Massie B. Miller F.D. Kaplan D.R. Neuron. 2000; 27: 265-277Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar). Neurotrophins, Antibodies, and Inhibitors—Reagents were purchased from the following companies: NGF, Cedarlane, Hornby, Ontario, Canada; brain-derived neurotrophic factor, PeproTech, Rocky Hill, NY; anti-β-galactosidase, anti-phospho-ERK, anti-phospho-p38 MAPK, and U0126, Promega Inc., Madison, WI; polyclonal anti-active JNK, BioSource, Camarillo, CA; anti-phospho Akt phosphorylated serine 473, Cell Signaling, Beverly, MA; polyclonal anti-ERK-1, anti-JNK-1, anti-Bcl-2, anti-Bcl-XL, anti-p53 (FL393) and anti-p53 CA; and Cell and NY; and and CA; and and Z-VAD-fmk, Trk Kaplan L. S. Kaplan D.R. Neuron. Full Text PDF PubMed Scopus Google Scholar) and TrkA Neuron. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) were previously and or human T. Kaplan D.R. Neuron. 1994; Full Text PDF PubMed Scopus Google Scholar) at extracellular with a by a were into the and into cells, and were amplified and as previously described B. J. N. J. Y. 1995; 13: Google Scholar, R. Miller F.D. Kaplan J. Neurosci. 1999; PubMed Google Scholar). wild-type or TrkB, GFP, or were described in (19Atwal J.K. Massie B. Miller F.D. Kaplan D.R. Neuron. 2000; 27: 265-277Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar), whereas Bcl-XL or wild-type p53 were described in J. Kaplan D.R. Miller F.D. J. Cell Biol. PubMed Scopus Google Scholar). and were a from A. H. N. A. E. Full Text Full Text PDF PubMed Scopus Google Scholar). was by the at for NB cells were and in with or survival and for were with at the multiplicity of and NGF and brain-derived neurotrophic factor and and were at the of NB cells for were with neurotrophin for at and and Trk proteins were and for in and for protein as described (5Kaplan D.R. Matsumoto K. Lucarelli E. Thiele C.J. Neuron. 1993; 11: 321-331Abstract Full Text PDF PubMed Scopus (311) Google Scholar). Trk in neurons was as described previously I. J. C. C. Kaplan Miller F.D. J. Cell Biol. 1997; PubMed Scopus Google Scholar). cell were a to or and proteins were a to the was with The for p53 were to the of the were in the of for the with in for and in for 1 at were with in at and with to for 1 at were with and were and were as previously described K. Miller F.D. Kaplan D.R. J. Neurosci. 2002; PubMed Google Scholar). were the Inc., and were the were and was with the TrkA was expressed by in two human NB cell lines derived from malignant tumors, and NGP (16Ciccarone V. Spengler B.A. Meyers M.B. Biedler J.L. Ross R.A. Cancer Res. 1989; 49: 219-225PubMed Google Scholar, G.M. Sekhon G. Goldstein M.N. Cancer. 1977; 40: 2256-2263Crossref PubMed Scopus (294) Google Scholar). of cell lines MYCN amplification and not TrkA or TrkB (16Ciccarone V. Spengler B.A. Meyers M.B. Biedler J.L. Ross R.A. Cancer Res. 1989; 49: 219-225PubMed Google Scholar, M. K. J.M. Brodeur G. Goldstein M. J. PubMed Scopus Google Scholar). wild-type human TrkA, or a human TrkA a mutation at T. Kaplan D.R. Neuron. 1994; Full Text PDF PubMed Scopus Google Scholar) were The TrkA proteins were expressed from a B. J. N. J. Y. 1995; 13: Google Scholar). that wild-type or TrkB (19Atwal J.K. Massie B. Miller F.D. Kaplan D.R. Neuron. 2000; 27: 265-277Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar) were also used to NB cells. with the expressed TrkA or TrkB, as by Trk of from cells with In cells with the and with the TrkA or TrkB NGF or brain-derived neurotrophic factor, TrkA and TrkB were expressed and as and and were also expressed at levels similar to wild-type at the used The was to or by at this TrkA expressed in NB cells is than the levels of TrkA in cultured sympathetic neurons indicating that TrkA was not TrkA expression was observed in the of with a to the TrkA expression we not in We whether TrkA expression would the survival or growth of the NB cell TrkA, TrkB, and were expressed in and NGP cell lines and survival by both and and at The survival of cells was by as with cells as by In contrast, the expression of TrkB, or cell survival. The cell of TrkA was in both and NGP cells, with cell of observed at as by and The cell at whether this of TrkA expression was to TrkA and not to a in the the TrkA was to of NGP cells. This TrkA-induced cell whether TrkA caused apoptotic cell were at following TrkA or of NGP cells. of the cells were by of TrkA whereas cells were observed in cells with the This was with Thus, TrkA, and not TrkB or TrkA induces the apoptotic cell of NB cells. of is that expression of TrkA via induce apoptosis of cell We whether TrkA expression would induce the of sympathetic neurons, which is derived from the precursor cells as NB is to from G.M. Cancer. PubMed Scopus Google Scholar). neurons isolated from the of were for in NGF and with TrkA or cells were of NGF, and for a in NGF, and were TrkA, when expressed at levels than TrkA not the survival of the neurons. the TrkA enhanced the survival of neurons in the or in low of NGF that not survival likely the of TrkA observed at high expression levels Kaplan L. S. Kaplan D.R. Neuron. Full Text PDF PubMed Scopus Google Scholar). Thus, elevated levels of TrkA mediate the apoptosis of NB cells and the survival of non-transformed neurons. We asked whether TrkA would induce apoptosis by as of activity, and by the of PARP, a target of NGP cells with NGF were with TrkA and by with to this was by and increased to levels at and This was to TrkA, expression resulted in at the This result was by for the of in NGP cells Similarly, the of was observed by and increased to whether cell by TrkA was caspase cells were with the caspase inhibitor prevented the of and by TrkA 1 and and cell by TrkA expression of proteins as Bcl-XL has been shown to 2000; PubMed Scopus Google Scholar). TrkA induces via the we that overexpression of Bcl-XL TrkA-induced cell death. NGP cells were with Bcl-XL or with The overexpression of Bcl-XL was by Bcl-XL expression prevented TrkA-induced and and cell by as with cells with TrkA and These results suggest that TrkA induces apoptosis in part by modulating the levels of In of this expression of TrkA, not via in NGP cells resulted in a suppression of protein levels as observed TrkA expression not the levels of or Bcl-XL TrkA Thus, TrkA may induce apoptosis is by the suppression of the levels of the protein We asked whether were in the of proteins in NB cells TrkA, which induces apoptosis, and TrkB, which does NB cells were with TrkA or TrkB, and the of and (14Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1653) Google Scholar), was in NGF or brain-derived neurotrophic factor by of cell with to phosphorylated and or TrkA and TrkB resulted in the of both Akt and to similar and TrkA expression resulted in in were observed in or cells with NGF or brain-derived neurotrophic factor for not These results suggest that TrkA may induce apoptosis by a this NGP cells were with the inhibitor U0126, and cell survival was for the of not of indicating that in not cell by TrkA in NGP cells as by or MAPK is not required for TrkA-induced cell death. The is important in sympathetic neurons (14Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1653) Google Scholar). We asked whether TrkA would induce the of in NB cells. NGP cells were with TrkA or for and with NGF for or to a and for that TrkA not induce the of indicating that are likely not involved in NB cell death. We also p38 MAPK activity, which is required for TrkA-induced apoptosis of cells C. Y. Cancer Res. 2002; 62: Google Scholar). in p38 MAPK by a and was observed in NGP cells with TrkA or not Thus, TrkA to induce a p38 MAPK, and cell death. An important of is the p53 tumor Most from patients wild-type p53 K. M. J.M. L. J. Brodeur G.M. J. P. Cancer Res. 1993; Google Scholar, H. Y. M. K. Y. S. R. K. T. M. Cancer Res. 1993; Google Scholar, J. H. Cancer Res. 1993; Google Scholar), and p53 is frequently in the of NB cells from its transcriptional M. J. G. S. A. 1995; PubMed Scopus Google Scholar, R. B. M. G. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar). whether TrkA p53 expression levels and/or we the protein levels of p53 following TrkA expression by or with TrkA, not in p53 levels that was observed at and and of a in p53 levels regression for or by for In that was to of with cells and The levels of a protein of a is by p53, were also increased by TrkA expression and In contrast, p53 levels were by TrkA expression in sympathetic neurons in levels of NGF that not survival The in p53 levels in NB cells were by NGP cells with anti-p53 at p53 levels were in than in cells and levels of p53 in the as with cells Thus, p53 may a of TrkA-induced NB cell death. whether p53 is required for NB cell two of were we asked whether TrkA would induce the of MYCN amplified SK-N-BE(2) neuroblastoma cells that a p53 M. H. A. L. J.C. A. A. P. J.M. X. P. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). SK-N-BE(2) or NGP wild-type p53 M. J. Am. J. Pathol. 2001; Full Text Full Text PDF PubMed Scopus Google cells were with TrkA, wild-type p53, or for in the of NGF, and cell was TrkA was expressed at and as a in the SK-N-BE(2) cells, as by of with two and by with and overexpression of wild-type p53 was sufficient to induce expression in both cell lines, TrkA was to protein levels in SK-N-BE(2) cells not p53 expression and cell in SK-N-BE(2) and NGP cells, at which increased to and by overexpression of TrkA in NGP cells cell TrkA expression in SK-N-BE(2) cells not result in in cell as with or cells at These results suggest that TrkA a wild-type p53 to induce the of NB cells. We whether expression of a dominant inhibitory of p53 A. H. N. A. E. Full Text Full Text PDF PubMed Scopus Google Scholar), NB cell death. of NGP cells with or to with TrkA prevented and NGP cells from TrkA-induced and Similarly, of E1B55K, which the of p53 J. Kaplan D.R. Miller F.D. J. Cell Biol. PubMed Scopus Google Scholar), with TrkA TrkA-induced cell results that expression of TrkA in NB cells results in the of apoptosis in a In this we show that expression of in two NB cell lines from poor prognosis tumors that not TrkA, induces apoptosis. TrkA and enhanced p53 protein levels and of a or of p53 NB cells from cell two TrkA induces apoptosis. The of apoptosis was expression of levels of TrkA and wild-type or TrkB not induce apoptosis. The also apoptosis, TrkA or GFP, and cell survival when expressed additional TrkA was by in sympathetic neurons. In to the apoptotic of TrkA in NB cells, TrkA expression in neurons enhanced and survival. TrkA to a of apoptosis in NB cells. This result from that TrkA overexpression the growth arrest and not the of NB cells (11Chen J. Chattopadhyay B. Venkatakrishnan G. Ross A.H. Cell Growth & Differ. 1990; 1: 79-85PubMed Google Scholar, 12Matsushima H. Bogenmann E. Mol. Cell. Biol. 1993; 13: 7447-7456Crossref PubMed Scopus (88) Google Scholar, E. Kaplan Thiele C.J. J. Cancer. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Ross A.H. 1995; 10: Google Scholar). An explanation for results may the used to In the TrkA was expressed by which would apoptotic cells, whereas in expression for and of apoptotic cells. were TrkA induce apoptosis, the suppression of Bcl-2, and the in p53 levels. might for TrkA the levels of Bcl-2, a protein for cell 2000; PubMed Scopus Google Scholar). TrkA caused the of p53, and p53 has been to V. D.S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. 2001; PubMed Scopus Google Scholar). TrkA, through its p53, the expression of the by which TrkA the levels of is by of caspase-3. is a target of Y. PubMed Scopus Google Scholar), and of by to in caspase R. M.B. A. K. J.M. 1997; PubMed Scopus Google Scholar). 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M. H. J. R. Brodeur G.M. L. Eggert A. PubMed Scopus Google Scholar, S. J. PubMed Scopus Google Scholar). We are the TrkA that to enhanced p53 expression. are p53 mediate cell death. p53 induce the of as and in the of from the and the of p53 at the to induce the of In this we show that following the in p53, the levels of a p53 also that p53 as a the levels of were not elevated following TrkA consistent with the of M. J. Am. J. Pathol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that NGP cells with p53 and not levels. In NB cells, it is likely that p53 induces apoptosis by a the expression of the dominant with a mutation in the or TrkA-induced cell death. TrkA and not TrkB caused the of NB cells. The we observed in the proteins by was a of by suppression of not cell and TrkA not p38 MAPK activity, which occurs in cells TrkA C. Y. Cancer Res. 2002; 62: Google Scholar, T.T. Trojanowski J.Q. Lee V.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This result is consistent with the of Chou T.T. Trojanowski J.Q. Lee V.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T.T. Trojanowski J.Q. Lee V.M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that TrkA-induced medulloblastoma apoptosis is of JNK, and p38 it is that TrkA induces a and/or that would for TrkA-induced apoptosis, as it has been for T.T. Trojanowski J.Q. Lee V.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). TrkA expression has been to a in the spontaneous regression of NB tumors A. Cancer Lett. 2001; PubMed Scopus Google Scholar). Our results suggest that TrkA expression may malignant neuroblastoma tumors to not by inducing differentiation as previously described (12Matsushima H. Bogenmann E. Mol. Cell. Biol. 1993; 13: 7447-7456Crossref PubMed Scopus (88) Google Scholar, 13Lavenius E. Gestblom C. Johansson I. Nanberg E. Pahlman S. Cell Growth & Differ. 1995; 6: 727-736PubMed Google Scholar), also by stimulating apoptosis. of of elevated TrkA expression may why TrkA is a good prognosis marker for novel the of TrkA or that TrkA might to patients with aggressive We C. for and P. for and and L. for We M. R. and the members of the Miller and Kaplan for and with

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