Abstract
Several studies have recently demonstrated that human gliomas express Fas, Fas ligand (FasL), Bcl-2 and TGFβ2 at some degree. These factors are considered to interact with apoptotic processes and to have immuno-reactive potential. Their role for tumor evasion from the immune surveillance is currently under examination. To date, there is only limited information about the definite expression patterns of these four factors in human gliomas, particularly in pilocytic astrocytoma (PA) and recurrent tumors.
We analyzed 75 human gliomas for the immunohistochemical expression of Fas, FasL, Bcl-2, and TGFβ2: (1) 25 PAs (WHO grade I), (2) 25 primary glioblastomas (WHO grade IV), and (3) 25 paired initial and recurrent glioblastomas (WHO grade IV), respectively.
Co-expression of all four factors was present in the majority of specimens, i.e. in 72% (18/25) of PAs and 88% (47/50) of primary glioblastomas. Pilocytic astrocytomas showed significantly higher scores of TGFβ2 expression (p < 0.05) and significantly lower Fas, Fas ligand and Bcl-2 scores (p < 0.05) than glioblastomas. There were no significant expression differences in initial versus recurrent glioblastoma specimens. Likewise, no significant correlation was observed between protein expression and clinical parameters, i.e. total survival time or progression free survival time, as documented by Kaplan–Meier method and log rank-test.
In conclusion, Fas, FasL, Bcl-2 and TGFβ2 are differently expressed in PAs versus glioblastomas. These factors, however, are not associated with patient prognosis. The broad co-expression of these factors may enable new therapeutic approaches in the future.
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References
Parney IF, Hao C, Petruk KC: Glioma immunology and immunotherapy. Neurosurgery 46: 778–792, 2000
Schmitt CA, Lowe SW: Apoptosis and therapy. J Pathol 187: 127–137, 1999
Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66: 233–243, 1991
Suda T, Takahashi T, Golstein P, Nagata S: Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169–1178, 1993
Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH: Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181: 71–77, 1995
Saas P, Walker PR, Hahne M, Quiquerez AL, Schnuriger V, Perrin G, French L, Van Meir EG, de Tribolet N, Tschopp J, Dietrich PY: Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest 99: 1173–1178, 1997
Didenko VV, Hop NN, Candace M, Baskin DS: Apoptosis of T lymphocytes invading glioblastomas multiforme: a possible tumor defense mechanism. J Neurosurg 96: 580–584, 2002
Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Med 3: 614–620, 1997
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X: Bid, a BCL 2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490, 1998
Massagué J: The TGF-beta family of growth and differentiation factors. Cell 49: 437–438, 1987
Frankel B, Longo SL, Ryken TC: Human astrocytomas coexpressing Fas and Fas ligand also produce TGFβ2 and Bcl-2. J Neuro-Oncol 44: 205–212, 1999
Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61: 215–225, 2002
Scherer HJ: Cerebral astrocytomas and their derivatives.Am J Cancer 40: 159–198, 1940
Husain N, Chiocca EA, Rainov N, Louis DN, Zervas NT: Co-expression of Fas and Fas ligand in malignant glial tumors and cell lines. Acta Neuropathol 95: 287–290
Gratas C, Tohma Y, Van Meir EG, Klein M, Tenan M, Ishii N, Tachibana O, Kleihues P, Ohgaki H: Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors. Brain Pathol 7: 863–869, 1997
Krishna M, Smith TW, Recht LD:Expression of bcl-2 in reactive and neoplastic astrocytes: lack of correlation with presence or degree of malignancy. J Neurosurg 83: 1017–1022, 1995
Hara A, Hirose Y, Yoshimi N, Tanaka T, Mori H: Expression of Bax and bcl-2 proteins, regulators of programmed cell death, in human brain tumors. Neurol Res 19: 623–628
Delgado MB, Anderson JR, Whittle IR, Wharton S B: Expression of Bcl-2 and Bax in oligodendrogliomas and their relationship to apoptosis. Neuropathol Appl Neurobiol 25: 400–407, 1999
Ehrmann J Jr, Rihakova P, Hlobilkova A, Kala M, Kolar Z: The expression of apoptosis-related proteins and the apoptotic rate in glial tumors of the brain. Neoplasma 47 (Suppl 3): 151–155, 2000
Nakasu S, Nakasu Y, Nioka H, Nakajima M, Handa J: Bcl-2 protein expression in tumors of the central nervous system. Acta Neuropathol (Berl) 88: 520–526, 1994
Ehrmann J Jr, Kolar Z, Vojtesek B, Kala M, Komenda S, Oulton A: Prognostic factors in astrocytomas: relationship of p53, MDM-2, BCL-2 and PCNA immunohistochemical expression to tumor grade and overall patient survival. Neoplasma 44: 299–304, 1997
Krajewski S, Krajewska M, Ehrmann J, Sikorska M, Lach B, Chatten J, Reed JC: Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol 150: 805–814, 1997
Martin S, Toquet C, Oliver L, Cartron PF, Perrin P, Meflah K, Cuillére P, Vallette FM: Expression of bcl-2, bax and bclxl in human gliomas: a re-appraisal. J Neuro-Oncol 52: 129–139, 2001
Frankel B, Longo SL, Ryken TC: Co-expression of Fas and Fas ligand in human non-astrocytic glial tumors. Acta Neuropathol 98: 363–366, 1999
Tachibana O, Nakazawa H, Lampe J, Watanabe K, Kleihues P, Ohgaki H: Expression of Fas/APO-1 during the progression of astrocytomas. Cancer Res 55: 5528–5530, 1995
Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A: Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 95: 2633–2643, 1995
Frankel B, Longo SL, Leach C, Canute GW, Ryken TC: Apoptosis and survival in high-grade astrocytomas as related to tumor Fas (APO-1/CD95) expression. J Neuro-Oncol 59: 27–34, 2002
Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD: Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science: 263: 1759–1762, 1994
Streffer JR, Schuster M, Zipp F, Weller M: Soluble CD95 (Fas/APO-1) in malignant glioma: (No) implications for CD95-based immunotherapy? J Neuro-Oncol 40: 233–235, 1998
Hamel W, Westphal M: Growth factors in gliomas revisited. Acta Neurochir 142: 113–138, 2000
Schiffer D, Cavalla P, Migheli A, Giordana MT, Chiadò-Piat L: Bcl-2 distribution in neuroepithelial tumors: an imunohistochemical study. J Neuro-Oncol 27: 101–109, 1996
Shinoura N, Yoshida Y, Nishimura M, Muramatsu Y, Asai A, Kirino T, Hamada H: Expression level of Bcl-2 determines anti-or proapoptotic function. Cancer Res 59: 4119–4128, 1999
Strik H, Deininger M, Streffer J, Grote E, Wickboldt J, Dichgans J, Weller M, Meyermann R: BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry 67: 763–768
Stark AM, Hugo HH, Witzel P, Mihajlovic Z, Mehdorn HM: Age-related expression of p53, Mdm2, EGFR and Msh2 in glioblastoma multiforme. Zentralbl Neurochir 64: 30–36, 2003
Stark AM, Witzel P, Strege RJ, Hugo H-H, Mehdorn HM: p53, mdm2, EGFR and msh2 expression in paired initial and recurrent glioblastoma multiforme. J Neurol Neurosurg Psychiatry 74: 779–783, 2003
Newcomb EW, Balla SK, Parrish CL, Hayes RL, Cohen H, Miller DC: bcl-2 protein expression in astrocytomas in relation to patient survival and p 53 gene status. Acta Neuropathol (Berl) 94: 369–375, 1997
Korshunov A, Golanov A, Sycheva R, Pronin I: Prognostic value of tumour associated antigen immunoreactivity and apoptosis in cerebral glioblastomas: an analysis of 168 cases. J Clin Pathol 52: 574–580, 1999
Fels C, Schäfer C, Hüppe B, Bahn H, Heidecke V, Kramm CM, Lautenschläger C, Rainov NG: Bcl-2 expression in higher-grade human glioma: a clinical and experimental study. J Neuro-Oncol 48: 207–216, 2000
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Strege, R.J., Godt, C., Stark, A.M. et al. Protein Expression of Fas, Fas Ligand, Bcl-2 and TGFβ2 and Correlation with Survival in Initial and Recurrent Human Gliomas. J Neurooncol 67, 29–39 (2004). https://doi.org/10.1023/B:NEON.0000021739.34343.75
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DOI: https://doi.org/10.1023/B:NEON.0000021739.34343.75