Abstract
Choroid plexus carcinomas are malignant brain tumors predominantly arising in young children. Because a prognostic role of p53 alterations has been demonstrated, further research into potential underlying mechanisms is essential. Our objective was, therefore, to investigate the role of p53 in the growth-inhibitory potential of a variety of anticancer agents in the rodent choroid plexus epithelial cell line Z310. Furthermore, association of p53 alterations with proliferative activity (Ki67/MIB1) in choroid plexus carcinoma samples (N = 20) was examined by use of immunohistochemistry. Silencing of TP53 expression did not significantly alter metabolic activity in Z310 cells and p53 protein expression status was not associated with increased proliferative activity in choroid plexus carcinomas. However, the growth-inhibitory activity of vincristine, doxorubicin, carboplatin, etoposide, and temozolomide was significantly impaired by silencing of TP53. In conclusion, these results indicate a potential predictive role of p53 in choroid plexus carcinomas. Alterations of p53 should be taken into account when evaluating the effect of anticancer agents in future clinical trials.
Similar content being viewed by others
References
Wolburg H, Paulus W (2010) Choroid plexus: biology and pathology. Acta Neuropathol 119:75–88
Paulus W, Brandner S (2007) Choroid plexus tumours. In: Louis DN, Ohgaki H, Wiestler O, Cavenee WK (eds) World Health Organization classification of tumors pathology and genetics of tumours of the nervous system. IARC Press, Lyon
Mazloom A, Wolff JE, Paulino AC (2010) The impact of radiotherapy fields in the treatment of patients with choroid plexus carcinoma. Int J Radiat Oncol Biol Phys 78:79–84
Wrede B, Liu P, Wolff JE (2007) Chemotherapy improves the survival of patients with choroid plexus carcinoma: a meta-analysis of individual cases with choroid plexus tumors. J Neurooncol 85:345–351
Lafay-Cousin L, Mabbott DJ, Halliday W, Taylor MD, Tabori U, Kamaly-Asl ID, Kulkarni AV, Bartels U, Greenberg M, Bouffet E (2010) Use of ifosfamide, carboplatin, and etoposide chemotherapy in choroid plexus carcinoma. J Neurosurg Pediatr 5:615–621
Berrak SG, Liu DD, Wrede B, Wolff JE (2011) Which therapy works better in choroid plexus carcinomas? J Neurooncol 103:155–162
El-Deiry WS (2003) The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22:7486–7495
Tabori U, Shlien A, Baskin B, Levitt S, Ray P, Alon N, Hawkins C, Bouffet E, Pienkowska M, Lafay-Cousin L, Gozali A, Zhukova N, Shane L, Gonzalez I, Finlay J, Malkin D (2010) TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 28:1995–2001
Wrede B, Hasselblatt M, Peters O, Thall PF, Kutluk T, Moghrabi A, Mahajan A, Rutkowski S, Diez B, Wang X, Pietsch T, Kortmann RD, Paulus W, Jeibmann A, Wolff JE (2009) Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study. J Neurooncol 95:383–392
Custodio G, Taques GR, Figueiredo BC, Gugelmin ES, Oliveira Figueiredo MM, Watanabe F, Pontarolo R, Lalli E, Torres LF (2011) Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil. PLoS ONE 6:e18015
Gozali AE, Britt B, Shane L, Gonzalez I, Gilles F, McComb JG, Krieger MD, Lavey RS, Shlien A, Villablanca JG, Erdreich-Epstein A, Dhall G, Jubran R, Tabori U, Malkin D, Finlay JL (2012) Choroid plexus tumors: management, outcome, and association with the Li-Fraumeni syndrome: the Children’s Hospital Los Angeles (CHLA) experience, 1991–2010. Pediatr Blood Cancer 58:905–909
Zheng W, Zhao Q (2002) Establishment and characterization of an immortalized Z310 choroidal epithelial cell line from murine choroid plexus. Brain Res 958:371–380
Hasselblatt M, Böhm C, Tatenhorst L, Dinh V, Newrzella D, Keyvani K, Jeibmann A, Buerger H, Rickert CH, Paulus W (2006) Identification of novel diagnostic markers for choroid plexus tumors: a microarray-based approach. Am J Surg Pathol 30:66–74
Judkins AR, Burger PC, Hamilton RL, Kleinschmidt-DeMasters B, Perry A, Pomeroy SL, Rosenblum MK, Yachnis AT, Zhou H, Rorke LB, Biegel JA (2005) INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J Neuropathol Exp Neurol 64:391–397
Tomm M, Koch A, Mertsch S, Wrede B, Jeibmann A, Wolff J, Paulus W, Hasselblatt M (2009) Role of Wnt inhibitory factor-1 and Wnt/wingless signaling in choroid plexus tumors. Pediatr Blood Cancer 53:1152–1155
Hasselblatt M, Mertsch S, Koos B, Riesmeier B, Stegemann H, Jeibmann A, Tomm M, Schmitz N, Wrede B, Wolff JE, Zheng W, Paulus W (2009) TWIST-1 is overexpressed in neoplastic choroid plexus epithelial cells and promotes proliferation and invasion. Cancer Res 69:2219–2223
Prasad P, Vasquez H, Das CM, Gopalakrishnan V, Wolff JE (2009) Histone acetylation resulting in resistance to methotrexate in choroid plexus cells. J Neurooncol 91:279–286
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Bernal SD, Shapiro HM, Chen LB (1982) Monitoring the effect of anti-cancer drugs on L1210 cells by a mitochondrial probe, rhodamine-123. Int J Cancer 30:219–224
Weyermann J, Lochmann D, Zimmer A (2005) A practical note on the use of cytotoxicity assays. Int J Pharm 288:369–376
Gieni RS, Li Y, HayGlass KT (1995) Comparison of [3H]thymidine incorporation with MTT- and MTS-based bioassays for human and murine IL-2 and IL-4 analysis. Tetrazolium assays provide markedly enhanced sensitivity. J Immunol Methods 187:85–93
Olivier M, Petitjean A, Marcel V, Petre A, Mounawar M, Plymoth A, de Fromentel CC, Hainaut P (2009) Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther 16:1–12
Lünenburger H, Lanvers-Kaminsky C, Lechtape B, Frühwald MC (2010) Systematic analysis of the antiproliferative effects of novel and standard anticancer agents in rhabdoid tumor cell lines. Anticancer Drugs 21:514–522
Weller M (1998) Predicting response to cancer chemotherapy: the role of p53. Cell Tissue Res 292:435–445
Lu C, El-Deiry WS (2009) Targeting p53 for enhanced radio- and chemo-sensitivity. Apoptosis 14:597–606
Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, Bouffet E, Malkin D, Hawkins C (2010) Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28:1345–1350
Gessi M, von Bueren AO, Rutkowski S, Pietsch T (2012) p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease. J Neurooncol 106:135–141
Meley D, Spiller DG, White MR, McDowell H, Pizer B, See V (2010) p53-mediated delayed NF-kappaB activity enhances etoposide-induced cell death in medulloblastoma. Cell Death Dis 1:e41
Ma CX, Cai S, Li S, Ryan CE, Guo Z, Schaiff WT, Lin L, Hoog J, Goiffon RJ, Prat A, Aft RL, Ellis MJ, Piwnica-Worms H (2012) Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models. J Clin Invest 122:1541–1552
Acknowledgments
Birgit Lechtape, Susanne Peetz-Dienhart, Tanja Plagemann, and Barbara Riesmeier provided expert technical assistance. Supported by Deutsche Krebshilfe (DK 108263) and Innovative Medizinische Forschung (IMF).
Conflict of interest
The authors declare they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Krzyzankova, M., Mertsch, S., Koos, B. et al. Loss of TP53 expression in immortalized choroid plexus epithelial cells results in increased resistance to anticancer agents. J Neurooncol 109, 449–455 (2012). https://doi.org/10.1007/s11060-012-0915-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-012-0915-3