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Cent Eur Neurosurg 2009; 70(3): 115-124
DOI: 10.1055/s-0029-1202356
Original Article

© Georg Thieme Verlag KG Stuttgart · New York

Apoptotic Proteins and Markers of Differentiation in Childhood Pineal Parenchymal Tumors: Relationships and Prognostic Value

Apoptotische Proteine und Differenzierungs-Marker bei parenchymatösen Tumoren der Pinealis in der Kindheit: Zusammenhänge und prognostischer WertW. Marcol1 , M. Mandera2 , W. Grajkowska3 , I. Malinowska-Kołodziej1 , E. Olakowska1 , A. Właszczuk1 , J. Lewin-Kowalik1
  • 1Department of Physiology, Medical Univeristy of Silesia, Katowice, Poland
  • 2Division of Neurosurgery, Medical Univeristy of Silesia, Katowice, Poland
  • 3Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland
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Publication History

Publication Date:
21 August 2009 (online)

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Abstract

Pineal parenchymal tumors (PPTs) in children and adolescents are uncommon and more data on their biological activity and behavior are still needed. The aim of our study was to estimate the expression and prognostic value of some proteins regulating apoptosis and cell cycle as well as being markers of cellular differentiation in PPTs. Tumor specimens obtained from 27 patients who underwent surgical treatment for PPTs were evaluated in immuno-histochemical analysis. The expression of Bcl-2, Bax, p53, NSE (neuron specific enolase), GFAP (glial fibrillary acidic protein), beta-III tubulin and nestin were studied. Co-localization of two chosen antibodies (e.g. Bcl-2/Bax, BCl-2/NSE, p53/NSE, etc.) was also made with a scanning confocal microscope. Histopathological examination revealed: 15 pineocytomas, 1 intermediately differentiated PPT and 11 pineoblastomas. For further analysis two groups were created: Group I: patients with pineocytoma or intermediately differentiated PPTs (16 cases) Group II: patients with pineoblastoma (11 cases). A statistically significant positive correlation between patients’ survival time and tubulin and NSE expression was found. Bcl-2, p53 and nestin correlated negatively with survival time.

Zusammenfassung

Pineale parenchymatöse Tumoren (PPTs) bei Kindern und Heranwachsenden sind selten und ergänzende Daten bezüglich ihrer biologischen Aktivität und ihres Verhaltens werden noch benötigt. Das Ziel unserer Untersuchung war es, die Expression und den prognostischen Wert einiger Proteine abzuschätzen, die die Apoptose und den Zellzyklus regulieren, ebenso wie Marker der zellulären Differenzierung bei PPTs. Tumorproben von 27 Patienten, die sich einer chirurgischen Behandlung unterzogen wegen ihrer PPTs, wurden mit immunhistochemischen Methoden untersucht. Die Expression von Bcl-2, Bax, p53, NSE (neuronspezifische Enolase), GFAP (gliales fibrilläres saures Protein), beta-III Tubulin und Nestin wurden untersucht. Die Ko-Lokalisation von ausgewählten Antikörperpaaren (z. B. Bcl-2/Bax, Bcl-2/NSE, p53/NSE, etc.) wurde auch im konfokalen Mikroskop untersucht. Die histopathologische Untersuchung ergab: 15 Pineozytome, 11 Pineoblastome, 1 intermediär differenzierter PPT. Zur weiteren Analyse wurden zwei Gruppen gebildet: 1. Patienten mit Pineozytom und intermediär differenzierten PPTs (16 Fälle), 2. Patienten mit Pineoblastom (11 Fälle). Eine statistisch signifikante positive Korrelation zwischen der Überlebenszeit der Patienten und der Expression von Tubulin und NSE wurde festgestellt. Bcl-2, p53 und Nestin korrelierten negativ mit der Überlebenszeit.

Key words

pineal parenchymal tumors - apoptosis - prognostic value - biological aggressiveness

Schlüsselwörter

pineale parenchymatöse Tumoren - Apoptose - prognostischer Wert - biologische Aggressivität

References

  • 1 Alderson LM, Castleberg RL, Harsh GR. et al . Human gliomas with wild type p53 express bcl-2.  Cancer Res. 1995;  55 999-1001
    Google Scholar
  • 2 Ali IU, Schweitzer JB, Ikejiri B. et al . Heterogeneity of subcellular localization of p53 protein in human glioblastomas.  Cancer Res. 1994;  54 1-5
    Google Scholar
  • 3 Bartek J, Bartkova J, Vojtesek B. et al . Abberant expression of the p53 oncoprotein is a common feature of a wide spectrum of human malignancies.  Oncogene. 1999;  6 1699-1703
    Google Scholar
  • 4 Bhargava V, Kell DL, Van De Rijn M. et al . Bcl-2 immunoreactivity in breast carcinoma correlates with hormone receptor positivity.  Am J Pathol. 1994;  145 535-540
    Google Scholar
  • 5 Bigner SH, Friedman HS, Vogelstein B. et al . Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts.  Cancer Res. 1990;  50 2347-2350
    Google Scholar
  • 6 Bruce JN, Stein BM. Surgical management of pineal region tumors.  Acta Neurochir (Wien). 1995;  134 130-135
    Google Scholar
  • 7 Bubendorf L, Sauter G, Moch H. et al . Prognostic significance of bcl-2 in clinically localized prostate cancer.  Am J Pathol. 1996;  148 1557-1565
    Google Scholar
  • 8 Castle VP, Heidelberger KP, Bromberg J. et al . Expression of the apoptosis-suppressing protein bcl-2 in neuroblastoma is associated with unfavorable history and N-myc amplification.  Am J Pathol. 1993;  143 1543-1550
    Google Scholar
  • 9 Chiou S-K, Rao L, White E. Bcl-2 blocks p53 dependent apoptosis.  Mol Cell Biol. 1994;  14 2556-2563
    Google Scholar
  • 10 Cho BK, Wang KC, Nam DH. et al . Pineal tumors: Experience with 48 cases over 10 years.  Child's Nerv Syst. 1998;  14 53-58
    Google Scholar
  • 11 Colombel M, Symmans F, Gil S. et al . Detection of the apoptosis suppressing oncogene bcl-2 in hormone refractory human prostate cancer.  Am J Pathol. 1993;  143 390-400
    Google Scholar
  • 12 Cory S, Harris AW, Strasser A. Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells.  Philos Trans R Soc Lond B Biol Sci. 1994;  345 289-295
    Google Scholar
  • 13 Deshmukh VR, Smith KA, Rekate HL. et al . Diagnosis and management of pineocytomas.  Neurosurgery. 2004;  55 349-355
    Google Scholar
  • 14 Drach LM, Kammermeier M, Neirich U. et al . Accumulation of nuclear p53 protein and prognosis of astrocytomas in childhood and adolescence.  Clin Neuropathol. 1996;  15 67-73
    Google Scholar
  • 15 Ellison DW, Seart PV, Gatter KC. et al . Apoptosis in cerebral astrocytic tumors and its relationship to expression of the bcl-2 and p53 proteins.  Neuropath Applied Neurobiol. 1995;  21 352-361
    Google Scholar
  • 16 Fauchon F, Jouvet A, Paquis P. et al . Parenchymal pineal tumors: a clinicopathological study of 76 cases.  J Radiation Oncology Biol Phys. 2000;  46 959-968
    Google Scholar
  • 17 Fels C, Schäfer C, Hűppe B. et al . Bcl-2 expression in higher-grade human glioma: a clinical and experimental study.  J Neuro-Oncol. 2000;  48 207-216
    Google Scholar
  • 18 Fèvre-Montange M, Grand S, Champier J. et al . Bcl-2 expression in a papillary tumor of the pineal region.  Neuropathology. 2008;  , Apr 10 [Epub ahead of print]
    Google Scholar
  • 19 Hara A, Hirose Y, Yoshimi N. et al . Expression of Bax and Bcl-2 proteins, regulators of programmed cell death, in human brain tumors.  Neurol Res. 1997;  19 623-628
    Google Scholar
  • 20 Hoffman HJ, Yoshida M, Becker LE. et al . Pineal region tumours in childhood.  Pediatr Neurosurg. 1994;  21 91-94
    Google Scholar
  • 21 Ikeda H, Hirato J, Akami M. et al . Bcl-2 oncoprotein and apoptosis in neuroblastoma.  J Pediatr Surg. 1995;  30 805-808
    Google Scholar
  • 22 Ishida H, Irie K, Itoh T. The prognostic significance of p53 and bcl-2 expression in lung adenocarcinoma and its correlation with ki-67 growth fraction.  Cancer. 1997;  80 1034-1045
    Google Scholar
  • 23 Ito Y, Matsuura N, Sakon M. Both cell proliferation and apoptosis significantly predict shortened disease-free survival in hepatocellular carcinoma.  Br J Cancer. 1999;  81 747-751
    Google Scholar
  • 24 Jakacki RI, Zeltzer PM, Boyett JM. et al . Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Children's Cancer Group.  J Clin Oncol. 1995;  13 1377-1383
    Google Scholar
  • 25 Jouvet A, Fèvre-Montange M, Besançon R. et al . Structural and ultrastructural characteristics of human pineal gland, and pineal parenchymal tumors.  Acta Neuropathol. 1994;  88 334-348
    Google Scholar
  • 26 Kaufmann SH, Vaux DL. Apoptosis anticancer drug resistance.  Oncogene. 2003;  22 7414-7420
    Google Scholar
  • 27 Kees UR, Spagnolo D, Hallam LA. et al . A new pineoblastoma cell line, PER-480, with der (10)t(10;17), der (16)t(1;16)and enhanced MYC expression in the absence of gene amplification.  Cancer Genet Cytogenet. 1998;  100 159-164
    Google Scholar
  • 28 Kikuchi Y, Dinjens WN, Bosman FT. Proliferation and apoptosis in proliferative lesions of the colon and rectum.  Virchows Arch. 1997;  431 111-117
    Google Scholar
  • 29 Kramer MH, Hermans J, Parker J. et al . Clinical significance of bcl-2 and p53 protein expression in diffuse large B-cell lymphoma: a population based study.  J Clin Oncol. 1996;  14 2131-2138
    Google Scholar
  • 30 Kumar P, Tatke M, Sharma A. et al . Histological analysis of lesions of the pineal region: a retrospective study of 12 years.  Pathol Res Pract. 2006;  202 85-92
    Google Scholar
  • 31 Louis DN, von Deimling A, Chung RY. et al . Comparative study of p53 gene and protein alterations in human astrocytic tumors.  J Neuropathol Exp Neurol. 1993;  52 31-38
    Google Scholar
  • 32 Marcol W, Kotulska K, Larysz-Brysz M. et al . Expression of Bcl-2 and Bax protein in normal pineal gland in children and young adult.  J Mol Histol. 2006;  37 5-7
    Google Scholar
  • 33 Marin MC, Hsu B, Stephens LC. et al . The functional basis of c-myc and bcl-2 complementation during multistep lymphomagenesis in vivo.  Exp Cell Res. 1995;  217 240-247
    Google Scholar
  • 34 Martin S, Toquet C, Oliver L. et al . Expression of bcl-2, bax and bcl-xl in human gliomas: A re-appraisal.  J Neuro-Oncol. 2001;  52 129-139
    Google Scholar
  • 35 MacDonald FE, Ironside JW, Gregor A. et al . The prognostic influence of bcl-2 in malignant glioma.  B J Cancer. 2002;  86 1899-1904
    Google Scholar
  • 36 Mena H, Nakazato Y, Jouvet A. et al .Pineal parenchymal tumours. In: Kleihues P, Cavenee WK. Tumours of the Nervous System. Lyon: IARC Press 2000: 115-121
    Google Scholar
  • 37 Miyake H, Hara I, Ymanaka K. et al . Overexpression of Bcl-2 enhances metastatic potential of human bladder cancer cells.  Br J Cancer. 1999;  79 1651-1656
    Google Scholar
  • 38 Muller W, Schneiders A, Hommel G. et al . Prognostic value of bcl-2 expression in gastric cancer.  Anticancer Res. 1998;  18 4699-4704
    Google Scholar
  • 39 Newcomb EW, Bhalla SK, Parrish CL. et al . Bcl-2 expression in astrocytomas in relation to patient survival and p53 gene status.  Acta Neuropathol. 1997;  94 369-375
    Google Scholar
  • 40 Newcomb EW, Cohen H, Lee SR. et al . Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2, or bcl-2 genes.  Brain Pathol. 1998;  8 655-667
    Google Scholar
  • 41 Papadimitriou JC, Castelli RJ, Simons JK. et al . Shifting of cytoplasmic pattern of bcl-2 expression in reactive and preneoplastic lesions to nuclear pattern in their malignant counterparts.  Cancer Detect Prev. 1999;  20 5-11
    Google Scholar
  • 42 Papierz W, Liberski PP. Nowotwory miąższu szyszynki.  Pol J Pathol. 2001;  53 113-116
    Google Scholar
  • 43 Reed JC, Miyashita T, Takayama S. et al . Bcl-2 family proteins: regulators of cell death in the pathogenesis of cancer and resistance to therapy (review).  J Cell Biochem. 1996;  60 23-32
    Google Scholar
  • 44 Rickert CH, Simon R, Bergmann M. et al . Comparative genomic hybridization in pineal parenchymal tumors.  , Genes Chromosomes and Cancer. 2000;  30 99-104
    Google Scholar
  • 45 Rieger L, Weller M, Bornemann A. et al . Bcl-2 family protein expression in human malignant glioma: a clinical-pathological correlative study.  J Neurol Sci. 1998;  155 68-75
    Google Scholar
  • 46 Sabapathy K, Klemm M, Jaenisch R. et al . Regulation of ES cell differentiation by functional and conformational modulation of p53.  EMBO J. 1997;  16 6217-6219
    Google Scholar
  • 47 Saylors 3rd RL, Sidransky D, Friedman HS. et al . Infrequent p53 gene mutations in medulloblastomas.  Cancer Res. 1991;  51 4721-4723
    Google Scholar
  • 48 Schiffer D, Cavalla P, Migheli A. et al . Bcl-2 distribution in neuroepithelial tumors: An immunohistochemical study.  J Neurooncol. 1996;  27 101-109
    Google Scholar
  • 49 Schiffer D, Cavalla P, Chio A. et al . Tumor cell proliferation and apoptosis in medulloblastoma.  Acta Neuropathol. 1994;  87 362-370
    Google Scholar
  • 50 Schild SE, Scheithauer BW, Schomberg PJ. et al . Pineal parenchymal tumors.  Cancer. 1993;  72 870-880
    Google Scholar
  • 51 Sembritzki O, Hagel C, Deppert W. et al . Cytoplasmic localization of wild-type p53 in glioblastomas correlates with expression of vimentin and glial fibrillary acidic protein.  NeuroOncology. 2002;  4 171-178
    Google Scholar
  • 52 Slooten HJ, Clahsen PC, van Dierendonck JH. et al . Expression of bcl-2 in node negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy.  Br J Cancer. 1996;  74 78-85
    Google Scholar
  • 53 Son EI, Kim IM, Kim DW. et al . Immunohistochemical analysis for histopathological subtypes in pediatric medulloblastomas.  Pathol Int. 2003;  2 67-73
    Google Scholar
  • 54 Sreekantaiah C, Hubert J, Brecher ML. et al . Interstitial deletion of chromosome 11q in a pineoblastoma.  Cancer Genet Cytogenet. 1989;  39 125-131
    Google Scholar
  • 55 Stiller CA, Nectoux J. International incidence of childhood brain and spinal tumors.  Internat J Epidemiol. 1994;  23 458-464
    Google Scholar
  • 56 Strik H, Deininger M, Streffer J. et al . Bcl-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy.  J Neurol Neurosurg Psych. 1999;  67 763-768
    Google Scholar
  • 57 Tsumanuma I, Sato M, Okazaki H. et al . The analysis of p53 tumor suppressor gene in pineal parenchymal tumors.  Noshuyo Byori. 1995;  12 39-45
    Google Scholar
  • 58 Tsumanuma I, Tanaka R, Washiyama K. Clinicopathological study of pineal parenchymal tumors: correlation between histopathological features, proliferative potential, and prognosis.  Brain Tumor Pathol. 1999;  16 61-68
    Google Scholar

Correspondence

Dr. W. MarcolMD, PhD 

Department of Physiology

Medical Univeristy of Silesia

Medykow 18

40-752 Katowice

Poland

Phone: +48/32/252 50 87

Fax: +48/32/252 60 77

Email: wmarcol@tlen.pl

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