Background and Methods The nerve growth factor receptor is expressedin some neuroblastomas, in which its primary component is encodedby the TRK proto-oncogene. To determine the relation of theexpression of TRK messenger RNA in neuroblastomas to other clinicaland laboratory variables, we studied frozen tumor samples from77 patients. In addition, we tested two primary neuroblastomasthat expressed TRK for responsiveness to nerve growth factor.
Results TRK expression strongly correlated with favorable tumorstage (I, II, and IVS vs. III and IV), younger age (<1 yearvs. 1 year), normal N-myc copy number, and low level of N-mycexpression. N-myc amplification (indicated by a high copy number)correlated with advanced tumor stage, older age, an adrenalsite of the primary tumor, low level of expression of TRK, andhigh level of expression of N-myc. Analysis of five-year cumulative-survivalrates demonstrated an association of a very favorable outcomewith a high level of TRK expression (86 percent vs. 14 percent)and with normal N-myc copy number (84 percent vs. 0 percent).Univariate analysis showed that these two variables were themost powerful predictors of outcome (chi-square = 51.30, P<0.001;and chi-square = 93.61, P<0.001, respectively). TRK expressionstill had significant prognostic value when the analysis wasrestricted to tumors without N-myc amplification. In primarycultures of neuroblastoma cells expressing TRK, exposure tonerve growth factor induced early gene expression and neuriteoutgrowth, but deprivation of nerve growth factor led to neuronalcell death.
Conclusions A high level of expression of the TRK proto-oncogenein a neuroblastoma is strongly predictive of a favorable outcome.A tumor with a functional nerve growth factor receptor may bedependent on the neurotrophin nerve growth factor for survivaland may regress in its absence, allowing a new approach to thetreatment of certain patients with neuroblastoma. .
Neuroblastoma is one of the most common malignant tumors amongchildren, yet the prognosis of patients with advanced diseaseis still very poor. The tumor originates from the sympathoadrenallineage of the neural crest1. The ability to differentiate bothin vivo and in vitro is one of the most interesting characteristicsof neuroblastomas, and this differentiation may involve theinteraction between the neurotrophin nerve growth factor (NGF)and its receptor2,3,4,5,6,7,8,9,10,11,12. Morphologic differentiationinduced by NGF has been observed in a limited number of primarycultures of neuroblastoma,4,6 but most neuroblastoma cell linesare unresponsive to NGF5,8,10,11,12. In a previous study, wefound multiple defects of expression and function of a componentof the NGF receptor in neuroblastoma cell lines,11 but the roleof the NGF-receptor pathway in the pathogenesis of neuroblastomashas been uncertain.
There are two classes of NGF receptors that bind NGF with eitherhigh or low affinity13,14. The low-affinity NGF-receptor (LNGFR)gene encodes a transmembrane protein, which is glycosylatedso that it yields a protein of about 75 kd (p75LNGFR)15,16.However, no known biologic responses are mediated solely bythe LNGFR17. The high-affinity NGF receptor appears to be aheteromeric complex that includes p75LNGFR and p140 proto-TRK,the product of the proto-oncogene TRK (also known as TRKA)18,19.This transmembrane glycoprotein is a tyrosine kinase that isexpressed selectively in the developing nervous system20. Thebiologic responsiveness to NGF depends on interactions withp140proto-TRK, but at present it is unclear whether this proteinexerts full biologic activity alone or acts as part of a high-affinityreceptor21,22,23,24.
TRK is expressed in many primary neuroblastomas and is associatedinversely with amplification of the N-myc proto-oncogene25.We studied the expression of TRK and LNGFR and attempted torelate the expression of these genes to clinical and biologicvariables, to assess the importance of the expression of NGFreceptors in neuroblastomas. In addition, we tested the functionof the NGF receptor in vitro in primary neuroblastomas thatexpressed TRK. We found that TRK expression is a powerful prognosticmarker that identifies a favorable group of tumors. We alsofound that NGF induces terminal neuronal differentiation inthese cells, but that deprivation of NGF leads to neuronal celldeath.
Methods
Patients and Therapy
We studied tumors from 77 children with neuroblastomas thathad been diagnosed in Japan and the United States from 1982to 199125. Sixty-three patients were identified at Kyushu NeuroblastomaStudy Group institutions and cooperative hospitals in Japan;the tumors of 27 of these patients were found during a massscreening program for neuroblastoma26. Thirteen patients wereidentified at Washington University in St. Louis or at otherinstitutions of the Pediatric Oncology Group, and one was identifiedelsewhere25. The selection of tumors for study was based solelyon the availability of a sufficient amount of tumor tissue fromwhich to prepare DNA and messenger RNA (mRNA) for the analysesdescribed below.
All diagnoses of neuroblastoma were confirmed by histologicassessment of a tumor specimen obtained at surgery. The histologicfeatures of the tumors were classified as described previously27.There were 59 neuroblastomas and 18 ganglioneuroblastomas, allof which were considered neuroblastomas in these analyses. Thetumors were staged according to the system of Evans et al28.Twenty patients (13 identified by mass screening) had stageI tumors, 14 (9 identified by mass screening) had stage II tumors,15 (5 identified by mass screening) had stage III tumors, 16had stage IV tumors, and 12 had stage IVS tumors. In additionto the tumors from the 77 patients, ganglioneuromas from 5 patientswere included as differentiated tumors in the comparison ofgene expression with tumor histology, but these patients werenot included in the survival analysis.
Patients were treated according to previously described protocols29,30,31,32,33,34,35.Despite differences between the protocols for treating the Japanesepatients and those for treating the patients studied by thePediatric Oncology Group, the drugs and doses used in the protocolswere quite similar, and the stage-specific survival rates ofthe two groups did not differ significantly (data not shown).The median follow-up period after diagnosis was 36 months (range,8 to 116). None of the patients underwent bone marrow transplantation.
Tumor Specimens and Cell Lines
Sixty of the 77 neuroblastoma samples were obtained from untreatedpatients. Fifteen Japanese patients with advanced disease receivedone or two courses of chemotherapy before tumor removal. Twotumor samples were obtained from metastases (a lymph node anda liver nodule), and the rest were obtained from the primarytumors. The tumor tissues were immediately frozen and storedat -70 °C until used. Three human neuroblastoma cell lines-- SK-N-SH (NSH), SH-SY5Y (SY5Y), and NMB -- as well as a ratpheochromocytoma line, PC12, have been described previously36,37and were grown as described25.
Southern and Northern Blot Analyses
The Nu-myc copy number was determined by Southern blot analysis38,39.A normal N-myc copy number is defined as 1 copy per haploidgenome (i.e., 2 per cell); a copy number above 3 per haploidgenome was considered to indicate N-myc amplification, but mosttumors with such amplification had 50 to 100 copies or more38,39.Total RNA was extracted from 0.5 to 1.0 g of frozen tumor tissueor cultured cells40. Expression of TRK, LNGFR, S100, and N-mycmRNA was measured by Northern blot analysis, normalized to thelevel of expression of -actin, and quantitated in arbitrarydensity units25. For some analyses, the tumors were groupedinto those with a low level of expression (<100 density units)and those with a high level ( 100 density units).
The following probes were gifts: the TRK probe from Luis Parada,23the LNGFR probe from Moses Chao,15 and the N-myc probe fromJ. Michael Bishop38. Expression of S100- was used as a markerfor Schwann cells41. The S100- probe was prepared by polymerase-chain-reaction(PCR) amplification and subcloning, based on a published sequence42.PCR amplification with total human DNA as a template resultedin a 778-base-pair fragment (primers, 5'TCAAAGAGCAGGAGGTTGTG3'and 5'GACTTGAATCGCATGGGTCA3'). To assess the function of theNGF receptor in primary cultures, we measured the inductionof expression of the early-response genes FOS43,44,45 and NGFI-A46.All probes were labeled by means of the random-hexamer primertechnique47.
Primary Culture of Neuroblastoma
Tumor cells were dissociated from tumor tissue obtained at surgery6.Aliquots of cells in collagen-coated wells were divided intothree groups: a control group (in standard medium), an NGF-treatedgroup (with 100 ng of mouse NGF per milliliter), and an NGF-depletedgroup (with 40 units of anti-NGF antiserum per milliliter).The NGF and antiserum48 were provided by Eugene M. Johnson.The cells were grown at 37 °C, and the culture medium waschanged every two or three days. For the studies of expression,the cells were grown in standard medium for 36 hours, treatedwith NGF for 40 minutes, and then immediately harvested, frozen,and stored at -70 °C for analysis.
Statistical Analysis
Statistical analyses were performed at the Pediatric OncologyGroup Statistical Office with SAS software. Associations betweenpairs of categorical variables were assessed with Pearson'schi-square statistic. The continuous variables of groups werecompared by the Wilcoxon rank-sum test. Survival probabilitiesin various subgroups were estimated according to the methodof Kaplan and Meier49. Survival of groups was compared by log-ranktests,50 with adjustment for N-myc amplification by Cox regression51.
Results
Expression of TRK, LNGFR, and N-myc
Expression of TRK mRNA was detected in 70 of the 77 neuroblastomas(91 percent), and LNGFR was expressed in 67 (87 percent) (Figure 1).However, a high level of expression ( 100 density units)of TRK was observed in 82 percent (63 tumors), but comparablelevels of LNGFR expression were found only in 36 percent (28tumors). The median level of TRK expression in tumors in stagesI, II, and IVS was 1544 density units (46 tumors), whereas thatin tumors in stages III and IV was 402 density units (31 tumors)(P<0.001)(Figure 1A). Eleven tumors with N-myc amplification had an extremelylow median level of TRK expression (0 density units), as comparedwith tumors without amplification (1352 density units; P = 0.003).When tumors with N-myc amplification were excluded, there wasstill a significant difference between the two tumor-stage groupsin the level of TRK expression (P = 0.016).
Figure 1. Densitometric Analysis of Expression of TRK and LNGFR in mRNA in Tumor Samples from 77 Patients with Neuroblastomas, According to Tumor Stage and N-myc Copy Number.
The levels of expression of TRK and LNGFR were normalized to that of -actin and measured in arbitrary density units. Horizontal lines represent group means. Diamonds represent patients identified by mass screening; squares, patients from whom samples were obtained at recurrence; and circles, all other patients, including those who have died (solid circles).
The median level of LNGFR expression was 22 density units instage I, II and IVS tumors (46 tumors) and 7 density units instage III and IV tumors (31 tumors) (Figure 1B). The tendencyof stage I, II, and IVS tumors to have higher levels of LNGFRexpression only approached significance (P = 0.076). Tumorswith N-myc amplification showed low levels of LNGFR expression,as compared with tumors without amplification (median, 3 densityunits [11 tumors] vs. 15 density units [66 tumors]; P<0.001).The expression of TRK in the reference neuroblastoma cell linesNSH, SY5Y, and NMB was 21, 110, and 0 density units, respectively,and the expression of LNGFR was 7, 6, and 0 density units, respectively(data not shown). N-myc was expressed at very high levels inall tumors with N-myc amplification (median level in 11 tumorswith amplification vs. median in 66 without amplification, 940vs. 10 density units; P<0.001). However, a moderate levelof expression was also observed in some tumors without amplification,and the level of expression was independent of tumor stage.The pattern of expression of TRK, LNGFR, and N-myc in tumorsidentified by mass screening was not significantly differentfrom that in tumors diagnosed because of clinical symptoms.
Age, Tumor Histology, and Pattern of Gene Expression
We analyzed the relation between the patient's age, the histologicgrade of differentiation, and the expression of TRK, LNGFR,S100-, and N-myc. The expression of S100- was considered a markerof Schwann cells, which are found frequently in differentiatedganglioneuroblastomas and ganglioneuromas41. Among the tumorsfrom infants (patients less than one year old), histologicallyundifferentiated neuroblastomas accounted for 88 percent oftumors (42 of 48), although almost all such tumors are curable.The TRK proto-oncogene was expressed strongly in 94 percent(45) of these tumors, whereas LNGFR was expressed strongly inonly 33 percent (16 tumors). Nevertheless, there was no correlationbetween the histologic grade of differentiation and the levelof expression of TRK, LNGFR, S100-, and N-myc in the infants.
In contrast, the proportion of histologically differentiatedganglioneuromas and ganglioneuroblastomas was higher (50 percent,or 17 of 34 tumors) among patients more than one year of age.The level of expression of LNGFR and S100- was high among differentiatedtumors (P = 0.012 and P<0.001, respectively), whereas thelevel of N-myc was high among undifferentiated tumors (P = 0.019).Interestingly, the level of expression of TRK did not correlatesignificantly with the histologic grade of differentiation (P>0.1).The five ganglioneuromas were obtained from patients more thanone year of age, and all expressed both LNGFR and S100- strongly,but they did not express N-myc.
Gene Expression and Survival
The cumulative-survival curves in the groups with high and lowlevels of expression of TRK and LNGFR, as well as amplificationand expression of N-myc, are shown in Figure 2. The expressionof TRK correlated strongly with survival (Figure 2A) (P<0.001):the five-year cumulative-survival rate of the group with a highlevel of TRK expression was 86 percent, whereas that of thegroup with a low level of TRK expression was 14 percent. N-mycamplification correlated significantly with poor survival (P<0.001)(Figure 2B). Although survival was significantly better whenthe level of expression of LNGFR was high (Figure 2C) and thatof the expression of N-myc was low (Figure 2D), the prognosticpower of these biologic variables was not as great as that ofTRK expression or N-myc amplification (see below).
Figure 2. Cumulative-Survival Curves of Patients with Neuroblastoma, According to Expression of TRK, LNGFR, and N-myc mRNA and N-myc Amplification.
The Kaplan-Meier curves show the probability of survival in terms of the level of expression of TRK, LNGFR, and N-myc and the N-myc copy number. High levels of mRNA expression were defined as values 100 density units, and low levels as values <100. The survival curves were analyzed by the Mantel-Haenszel log-rank test.
We analyzed survival according to the pattern of expressionof both TRK and LNGFR. The group with high levels of expressionof both TRK and LNGFR had the best five-year survival rate (92percent), and the group with low levels of expression of bothgenes had the worst (9 percent). However, neither high nor lowlevels of expression of LNGFR significantly influenced survivalafter correction for the expression of TRK (data not shown).Figure 3 shows the effect of the combination of TRK expressionand N-myc amplification on cumulative survival. The group withhigh levels of TRK expression and no N-myc amplification (62patients) had a cumulative five-year survival of 87 percent.Four patients whose tumors had a normal N-myc copy number hada low level of expression of TRK, and their survival was significantlyworse than that of the group with a high level of TRK expression(P = 0.03) (Figure 3). All 11 patients with N-myc amplificationhad low levels of expression of TRK except 1 patient (not shownin Figure 3), who had high levels of TRK expression. The tumorof this patient was regressing at the time of biopsy, but arecurrence was fatal25,52; all 11 of these patients died withintwo years after diagnosis.
Figure 3. Cumulative Survival According to Expression of TRK mRNA and N-myc Amplification Combined.
A patient with stage IVS neuroblastoma whose tumor had a high level of expression of TRK and N-myc amplification died 11 months after diagnosis52 and is not represented in this figure. Survival was significantly better in the group with high levels of TRK expression and no N-myc amplification than in the group with low levels of TRK expression and no N-myc amplification (P = 0.03) or the group with low levels of TRK expression and N-myc amplification (P<0.001). Survival was significantly better in the group with low levels of TRK expression and no N-myc amplification than in the group with low levels of TRK expression and N-myc amplification (P = 0.005).
We analyzed the effect on survival of the expression of TRK,LNGFR, and S100-, as compared with the effect of the patient'sage, tumor stage, primary tumor site, and tumor histology, aswell as amplification and expression of N-myc (Table 1). Onthe basis of this univariate analysis, N-myc amplification andTRK expression were significant factors (chi-square = 93.61and 51.30, respectively; P<0.001 for each), as were stageand age (chi-square = 23.30 and 21.67, respectively; P<0.001for each); tumor site, N-myc expression, and LNGFR expressionwere not as significant (Table 1). When outcome was adjustedfor the effect of N-myc amplification, TRK expression was nolonger significant among all the patients studied, but it didremain significant among the patients without N-myc amplification(chi-square = 4.56; P = 0.03); stage and age remained significant(Table 1), but after adjustment for stage no other factors hadprognostic value.
Table 1. Univariate and Multivariate Analysis of Clinical and Laboratory Variables and Survival in 77 Patients with Neuroblastomas.
Expression and Function of NGF Receptor in Primary Tumors
The above studies indicated that most neuroblastomas from patientswith a favorable prognosis (particularly infants) had high levelsof expression of both TRK and LNGFR. To determine whether theNGF-receptor pathway was functional in these tumors, we establishedprimary cultures of neuroblastomas from two such patients. Patient1 was a 14-month-old girl with a posterior mediastinal mass,and Patient 2 was a 2-month-old girl with an intrapelvic tumor.
The levels of TRK expression and LNGFR expression in tumor tissuefrom Patient 1 were 411 and 1260 density units, respectively,and the levels in tissue from Patient 2 were 1307 and 580 densityunits, respectively. The adherent tumor cells from Patient 1in medium containing NGF developed substantial neurite extensionby day 6, which reached a maximum on day 13, and the differentiatedcells survived more than one month (data not shown). However,in medium depleted of NGF some adherent cells extended a fewshort neurites, but all cells ultimately died within two weeksin vitro.
The primary tumor cells from Patient 2 responded to NGF morequickly. The NGF-treated cells showed numerous neurites by day2, which grew further by day 7, and these cells survived morethan 100 days. In addition, NGF induced the expression of theearly-response genes, FOS and NGFI-A, in these cells (Figure 4).However, tumor cells cultured in standard medium or in NGF-depletedmedium began dying after day 4, and all had died by day 14.The tumor cells grown in NGF-depleted medium died more rapidlythan those grown in standard medium.
Figure 4. Induction of the Expression of FOS and NGFI-A by NGF Treatment of Primary Culture Cells from Patient 2.
The patient's cells were cultured in the standard medium for 1 1/2 days before they were treated with NGF (100 ng per milliliter, incubated for 40 minutes at 37 °C). PC12 cells and NSH cells were treated as positive and negative controls, respectively.
Discussion
Neuroblastomas are derived from the sympathoadrenal progenitorsof the neural crest. The expression of the components of theNGF receptor in these progenitors, as well as their responsivenessto NGF, is developmentally regulated. The earliest progenitorsexpress neither component,53,54 but subsequently NGF receptoris expressed on migrating neural-crest cells55. Identifiablefetal sympathetic ganglia and adrenal medullary cells bind NGFwith high and low affinity and presumably express both TRK andLNGFR20,55,56,57,58,59. These cells soon become dependent onNGF for their survival, and they differentiate in its presence.However, complete neuronal differentiation may require additionalfactors53,54. Deprivation of neurotrophic factor may lead toprogrammed cell death at this stage60,61. Finally, cells thatundergo morphologic differentiation become relatively independentof NGF for their survival and will not die rapidly if it iswithdrawn61,62,63.
Our studies indicate that the level of TRK expression is highin the majority of neuroblastomas, particularly in those ofinfants and patients in the earlier stages of disease. In addition,a high level of TRK expression correlates strongly with a favorableoutcome. However, the pattern of expression of LNGFR and itsprognostic importance are less clear. The heterogeneity of expressionof TRK and LNGFR in neuroblastomas is consistent with the patternof expression in sympathoadrenal precursors, and it may reflectarrested differentiation at these stages, as suggested by otherinvestigators using different developmental markers64,65.
We observed several clear patterns of expression of neural-crest-relatedgenes that correlated with distinct histologic patterns andclinical behaviors of the tumors. At the end of the spectrumcontaining the most immature tumors were neuroblastomas withN-myc amplification. These tumors had high levels of N-myc butlow levels or no expression of TRK, LNGFR, and S100-, and theywere the most undifferentiated tumors histologically. Thesetumors are most likely to become established cell lines in vitro,and they appear to be neither responsive to NGF nor dependenton it for survival. They may mimic the most immature sympathoadrenalprecursors53,54.
The next group was made up of tumors without N-myc amplificationthat expressed TRK, usually with LNGFR. Characteristically,neuroblastomas in infants were undifferentiated histologically,but these tumors had the highest levels of TRK expression, usuallywith moderate levels of LNGFR expression. S100- expression usuallywas low or absent, a finding consistent with the paucity ofSchwann cells in these tumors. The level of N-myc expressionfrequently was high, especially in tumors of infants. Thesetumors probably express functional NGF receptors, which wouldmake at least some of them both dependent on NGF and responsiveto it. These conclusions are supported by our in vitro studies,in which the tumor cells responded to NGF by inducing early-responsegenes and by terminal differentiation in the sustained presenceof NGF. Furthermore, the cells died if NGF was absent or antiserumto NGF was present in the medium, probably as a result of programmedcell death triggered by deprivation of this neurotrophic factor60.
The end of the spectrum containing the most-differentiated tumorsis represented by ganglioneuromas, which were found exclusivelyin patients more than one year of age. These tumors were characterizedby high levels of expression of LNGFR and S100-, reflectingthe substantial Schwann-cell component. N-myc expression wasvery low or absent, and TRK expression was variable, perhapsreflecting the heterogeneity in the number of ganglion cellsin these tumors. The finding of ganglioneuromas exclusivelyin patients more than one year old may indicate that differentiationin vivo is a slower process or that other neurotrophic factorsare required.
A variety of other clinical and biologic variables have beenproposed as prognostic factors for neuroblastoma, includingcellular DNA content or chromosome number (ploidy) as a favorablemarker66,67,68,69,70 and N-myc amplification as a marker ofpoor outcome38,39,70,71,72,73. Since the level of TRK expressionwas high in infants with early-stage tumors, this may representa biologic mechanism that would explain the favorable behaviorof hyperdiploid tumors. Conversely, the virtual absence of TRKexpression in tumors with N-myc amplification25 may render thesecells unresponsive whether or not NGF is present.
Assessment of TRK expression and of N-myc copy number may providecomplementary prognostic information, which in turn may be helpfulin determining the most appropriate duration and intensity oftreatment. More important, both of these factors may have arole in the pathogenesis of neuroblastoma. Cells expressingfunctional NGF receptor may be susceptible to either programmedcell death leading to tumor regression, especially in infants,or to differentiation leading to a benign ganglioneuroma, especiallyin older children. Future therapeutic approaches may be aimedat activating or antagonizing the NGF-receptor pathway to inducedifferentiation or regression in these tumors. Tumors with N-mycamplification may be particularly aggressive because very highlevels of N-myc give them a growth advantage and may also blocktheir differentiation into NGF-dependent or NGF-responsive cells.Such a blockade would require some alternative approach to therapy.
Supported in part by grants (CA-49712, CA-39771, and CA-05587[to Dr. Brodeur]) from the National Cancer Institute, by a grant(to Dr. Nakagawara) from the National Cancer Institute-JapaneseFoundation of Cancer Research Cooperative Cancer Research Program,and by funds from the Ronald McDonald Children's Charities (toDr. Brodeur).
We are indebted to Drs. Keiichi Ikeda, Sachiyo Suita, HiroshiOhgami, Hideko Tasaka, Sumio Miyazaki, Yoshifumi Sera, HiroshiAkiyama, and Kiyoshi Kawakami (Kyushu Neuroblastoma Study Groupinstitutions), Dr. Takashi Yokoyama (Hiroshima University Hospital),Dr. Akira Kuwano (Yamaguchi University Hospital), Dr. KazuhiroKume (Matsuyama Red Cross Hospital), Drs. Paul Bowman, RandallCraver, Joseph Dickerman, Donald Fernbach, Vita Land, RuprechtNitchke, and Teresa Vietti (Pediatric Oncology Group institutions),and Dr. Audrey Evans (Children's Hospital of Philadelphia) forcontributing neuroblastoma samples for these studies; to HelenMarshall for technical assistance; and to Peter S. White, JillL. Hiemstra, and Richard B. Schuessler for advice.
Source Information
From the Department of Pediatrics, Washington University School of Medicine, St. Louis (A.N., M.A.-N., N.J.S., C.G.A., G.M.B.), the Pediatric Oncology Group Statistical Office, Gainesville, Fla. (A.B.C.), and the Pediatric Oncology Group, St. Louis (G.M.B., A.B.C.).
Address reprint requests to Dr. Brodeur at the Department of Pediatrics, Washington University School of Medicine, 1 Children's Place, St. Louis, MO 63110.
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1 year), normal N-myc copy number, and low level of N-myc expression. N-myc amplification (indicated by a high copy number) correlated with advanced tumor stage, older age, an adrenal site of the primary tumor, low level of expression of TRK, and high level of expression of N-myc. Analysis of five-year cumulative-survival rates demonstrated an association of a very favorable outcome with a high level of TRK expression (86 percent vs. 14 percent) and with normal N-myc copy number (84 percent vs. 0 percent). Univariate analysis showed that these two variables were the most powerful predictors of outcome (chi-square = 51.30, P<0.001; and chi-square = 93.61, P<0.001, respectively). TRK expression still had significant prognostic value when the analysis was restricted to tumors without N-myc amplification. In primary cultures of neuroblastoma cells expressing TRK, exposure to nerve growth factor induced early gene expression and neurite outgrowth, but deprivation of nerve growth factor led to neuronal cell death. 
-actin, and quantitated in arbitrary density units25. For some analyses, the tumors were grouped into those with a low level of expression (<100 density units) and those with a high level (
103,000 125I-
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