Abstract
CCAAT/enhancer binding protein (C/EBP) δ is a transcription factor which has been demonstrated to mediate the growth arrest of mammary and prostate cancer cell lines. It is induced by several stimuli including inflammatory cytokines. In this study, C/EBPδ immunohistochemical expression was assessed in 49 meningiomas of different histotype and grade and correlated with a variety of clinico-pathological data and with the overall and recurrence-free survival of the patients. Positive staining was observed in the nuclei of neoplastic cells in 22 out of the 49 cases analyzed. C/EBPδ expression was significantly associated with a low histological grade and proliferation index, reflected by low Ki-67 labeling index (LI) and mitotic activity, and with the presence of intra-tumoral inflammatory infiltrate and the absence of necrosis. In addition, the absence of C/EBPδ was significantly correlated with a shorter disease-free interval. Our findings suggest that C/EBPδ expression may prevent the development of recurrences by inhibition of neoplastic growth in meningiomas. If further studies confirm its induction by inflammatory mediators, this might be exploited in novel therapies to prevent recurrences in meningiomas.
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References
Lekstrom-Himes J, Xanthopoulos KG (1998) Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 273:28545–28548
O’Rourke R, Yuan J, DeWille JW (1997) CCAAT/enhancer binding protein-delta is induced in growth-arrested mouse mammary epithelial cells. J Biol Chem 272:6291–6296
Hutt JA, O’Rourke JP, DeWille JW (2000) Stat3 activates C/EBPd gene transcription in G0 growth arrested mouse mammary epithelial cells and in involuting mouse mammary gland. J Biol Chem 275:29123–29131
Gigliotti AP, Johnson PJ, Sterneck E, DeWille JW (2003) Nulliparous CCAAT/enhancer binding proteindelta (C/EBPdelta) knockout mice exhibit mammary gland ductal hyperplasia. Exp Biol Med 228:278–285
Thangaraju M, Rudelius M, Bierie B, Raffeld M, Sharan S, Hennighausen L, Huang AM, Sterneck E (2005) C/EBP δ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development 132:4675–4685
Sivko GS, DeWille JW (2004) CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. “Loss of function” alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines. J Cell Biochem 93:830–843
Sivko GS, Sanford DC, Dearth LD, Tang D, DeWille JW (2004) CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: II. Analysis of activating signal transduction pathways, transcriptional, post-transcriptional, and post-translational control. J Cell Biochem 93:844–856
Ikezoe T, Gery S, Yin D, O’Kelly J, Binderup L, Lemp N, Taguchi H, Koeffler HP (2005) CCAAT/enhancer-binding protein delta: a molecular target of 1, 25-dihydroxyvitamin D3 in androgen-responsive prostate cancer LNCaP cells. Cancer Res 1:4762–4768
Sanford DC, DeWille JW (2005) C/EBP δ is a downstream mediator of IL-6 induced growth inhibition of prostate cancer cells. Prostate 63:143–154
O’Rourke JP, Newbound GC, Hutt JA, DeWille JW (1999) C/EBP δ regulates mammary epithelial cell G0 growth arrest and apoptosis. J Biol Chem 274:16582–16589
Hutt J, DeWille JW (2002) Oncostatin M induces growth arrest of mammary epithelial cells via a CCAAT/enhancer binding protein delta dependent pathway. Mol Cancer Ther 1:601–610
Ramji DP, Foka P (2002) CCAAT/enhancer binding proteins: structure, function and regulation. Biochem J 365:561–575
Sundfeldt K, Ivarsson K, Carlsson M, Enerbäck S, Janson PO, Brännström M, Hedin L (1999) The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPbeta during epithelial tumour progression. Br J Cancer 79:1240–1248
Cardinaux JR, Allaman I, Magistretti PJ (2000) Pro-inflammatory cytokines induce the transcription factors C/EBPβ and C/EBPδ in astrocytes. Glia 29:91–97
Homma J, Yamanaka R, Yajima N, Tsuchiya N, Genkai N, Sano M, Tanaka R (2006) Increased expression of CCAAT/enhancer binding protein beta correlates with prognosis in glioma patients. Oncol Rep 15:595–601
Perry A, Louis DN, Scheithauer BW, Budka H, von Deimling A (2007) Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumors of the central nervous system. IARCC Press, Lyon, pp 164–172
Simpson D (1957) The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20:22–39
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM (1998) The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. Cancer 82:2262–2269
Kamitani H, Masuzwa H, Kanazawa I, Kubo T (2001) Recurrence of convexity meningiomas: tumour cells in the arachnoid membrane. Surg Neurol 56:228–235
Barresi V, Cerasoli S, Paioli G, Vitarelli E, Giuffrè G, Guiducci G, Tuccari G, Barresi G (2006) Caveolin-1 in meningiomas: expression and clinico-pathological correlations. Acta Neuropathol 112:617–626
Barresi V, Cerasoli S, Vitarelli E, Tuccari G (2007) Density of microvessels positive for CD105 (endoglin) is related to prognosis in meningiomas. Acta Neuropathol 114:147–156
Barresi V, Vitarelli E, Cerasoli S (2009) Semaphorin3A immunohistochemical expression in human meningiomas: correlation with the microvessel density. Virchows Arch 454:563–571
Billiard J, Humayahara Y, Wirens K, Centrella M, McCarthy TL, Rotwein P (2001) Regulated nuclear-cytoplasmic localization of CCAAT/enhancer binding protein δ in osteoblasts. J Biol Chem 276:15354–15361
Gery S, Tanosaki S, Hofmann WK, Koppel A, Koeffler HP (2005) C/EBPdelta expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation. Oncogene 24:1589–1597
Bovle-Walsh E, Hashim IA, Speirs V, Fraser WD, White MC (1994) Interleukin-6 (IL-6) production and cell growth of cultured human meningiomas: interactions with interleukin-1 beta (IL-1 beta) and interleukin-4 (IL-4) in vitro. Neurosci Lett 170:129–132
Todo T, Adams EF, Rafferty B, Fahlbusch R, Dingermann T, Werner H (1994) Secretion of interleukin-6 by human meningioma cells: possible autocrine inhibitory regulation of neoplastic cell growth. J Neurosurg 81:394–401
Kallio M, Sankila R, Hakulinen T, Jaaskelainen J (1992) Factors affecting operative and excess long-term mortality in 935 patients with intracranial meningioma. Neurosurgery 31:2–12
Perry A, Scheithauer BW, Stafford SL, Lohse CM, Wollan PC (1999) “Malignancy” in meningiomas: a clinico-pathological study of 116 patients, with grading implications. Cancer 85:2046–2056
Schrell UM, Koch HU, Marschalek R, Schrauzer T, Anders M, Adams E, Fahlbusch R (1998) Formation of autocrine loops in human cerebral meningioma tissue by leukemia inhibitor factor, interleukin-6, and oncostatin M: inhibition of meningioma cell growth in vitro by recombinant oncostatin M. J Neurosurg 88:541–548
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Barresi, V., Vitarelli, E., Cerasoli, S. et al. The cell growth inhibitory transcription factor C/EBPδ is expressed in human meningiomas in association with low histological grade and proliferation index. J Neurooncol 97, 233–240 (2010). https://doi.org/10.1007/s11060-009-0024-0
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DOI: https://doi.org/10.1007/s11060-009-0024-0