Skip to main content

Advertisement

SpringerLink
Log in

Multifarious proteomic signatures and regional heterogeneity in glioblastomas

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

To investigate the underlying intratumoral diversity of molecular profiles in glioblastomas, a proteomic approach was introduced to compare samples from regions of different histological grade. Using two-dimensional gel electrophoresis (2DE) with matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), we compared prospectively collected tissue samples of different histological grade areas of three glioblastoma patients. Consistent results showing relatively high expression of ubiquitin carboxyl-terminal esterase L1 in low-histological-grade areas (Grade 2 > Grades 3 and 4) and high expression of transthyretin in high-histological-grade areas (Grade 2 < Grades 3 and 4) were demonstrated. These results were confirmed by western blot (WB) analysis and immunohistochemical staining. This study provided the evidence of multifarious proteomic signatures according to regional and histological heterogeneity in glioblastomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Diehn M, Nardini C, Wang DS et al (2008) Identification of noninvasive imaging surrogates for brain tumor gene-expression modules. Proc Natl Acad Sci USA 105:5213–5218. doi:10.1073/pnas.0801279105

    Article  PubMed  CAS  Google Scholar 

  2. Earnest Ft, Kelly PJ, Scheithauer BW et al (1988) Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology 166:823–827

    PubMed  Google Scholar 

  3. Hobbs SK, Shi G, Homer R et al (2003) Magnetic resonance image-guided proteomics of human glioblastoma multiforme. J Magn Reson Imaging 18:530–536. doi:10.1002/jmri.10395

    Article  PubMed  Google Scholar 

  4. Van Meter T, Dumur C, Hafez N et al (2006) Microarray analysis of MRI-defined tissue samples in glioblastoma reveals differences in regional expression of therapeutic targets. Diagn Mol Pathol 15:195–205. doi:10.1097/01.pdm.0000213464.06387.36

    Article  PubMed  Google Scholar 

  5. Harada K, Nishizaki T, Ozaki S et al (1998) Intratumoral cytogenetic heterogeneity detected by comparative genomic hybridization and laser scanning cytometry in human gliomas. Cancer Res 58:4694–4700

    PubMed  CAS  Google Scholar 

  6. Loeper S, Romeike BF, Heckmann N et al (2001) Frequent mitotic errors in tumor cells of genetically micro-heterogeneous glioblastomas. Cytogenet Cell Genet 94:1–8. doi:10.1159/000048773

    Article  PubMed  CAS  Google Scholar 

  7. Shuangshoti S, Navalitloha Y, Kasantikul V et al (2000) Genetic heterogeneity and progression in different areas within high-grade diffuse astrocytoma. Oncol Rep 7:113–117

    PubMed  CAS  Google Scholar 

  8. Walker C, du Plessis DG, Joyce KA et al (2003) Phenotype versus genotype in gliomas displaying inter- or intratumoral histological heterogeneity. Clin Cancer Res 9:4841–4851

    PubMed  CAS  Google Scholar 

  9. Mariani L, Beaudry C, McDonough WS et al (2001) Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro. Clin Cancer Res 7:2480–2489

    PubMed  CAS  Google Scholar 

  10. Hoelzinger DB, Mariani L, Weis J et al (2005) Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia 7:7–16. doi:10.1593/neo.04535

    Article  PubMed  CAS  Google Scholar 

  11. Suzuki T, Maruno M, Wada K et al (2004) Genetic analysis of human glioblastomas using a genomic microarray system. Brain Tumor Pathol 21:27–34. doi:10.1007/BF02482174

    Article  PubMed  CAS  Google Scholar 

  12. Aghi M, Gaviani P, Henson JW et al (2005) Magnetic resonance imaging characteristics predict epidermal growth factor receptor amplification status in glioblastoma. Clin Cancer Res 11:8600–8605. doi:10.1158/1078-0432.CCR-05-0713

    Article  PubMed  CAS  Google Scholar 

  13. Necesalova E, Vranova V, Kuglik P et al (2007) Incidence of the main genetic markers in glioblastoma multiforme is independent of tumor topology. Neoplasma 54:212–218

    PubMed  CAS  Google Scholar 

  14. Glanz C, Rebetz J, Stewenius Y et al (2007) Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability. Neuropathol Appl Neurobiol 33:440–454. doi:10.1111/j.1365-2990.2007.00832.x

    Article  PubMed  CAS  Google Scholar 

  15. Whittle IR, Short DM, Deighton RF et al (2007) Proteomic analysis of gliomas. Br J Neurosurg 21:576–582. doi:10.1080/02688690701721691

    Article  PubMed  CAS  Google Scholar 

  16. Iwadate Y, Sakaida T, Hiwasa T et al (2004) Molecular classification and survival prediction in human gliomas based on proteome analysis. Cancer Res 64:2496–2501. doi:10.1158/0008-5472.CAN-03-1254

    Article  PubMed  CAS  Google Scholar 

  17. Schwartz SA, Weil RJ, Johnson MD et al (2004) Protein profiling in brain tumors using mass spectrometry: feasibility of a new technique for the analysis of protein expression. Clin Cancer Res 10:981–987. doi:10.1158/1078-0432.CCR-0927-3

    Article  PubMed  CAS  Google Scholar 

  18. Odreman F, Vindigni M, Gonzales ML et al (2005) Proteomic studies on low- and high-grade human brain astrocytomas. J Proteome Res 4:698–708. doi:10.1021/pr0498180

    Article  PubMed  CAS  Google Scholar 

  19. Furuta M, Weil RJ, Vortmeyer AO et al (2004) Protein patterns and proteins that identify subtypes of glioblastoma multiforme. Oncogene 23:6806–6814. doi:10.1038/sj.onc.1207770

    Article  PubMed  CAS  Google Scholar 

  20. Iwadate Y, Sakaida T, Saegusa T et al (2005) Proteome-based identification of molecular markers predicting chemosensitivity to each category of anticancer agents in human gliomas. Int J Oncol 26:993–998

    PubMed  CAS  Google Scholar 

  21. Kleinschmidt-DeMasters BK, Meltesen L, McGavran L et al (2006) Characterization of glioblastomas in young adults. Brain Pathol 16:273–286. doi:10.1111/j.1750-3639.2006.00029.x

    Article  PubMed  CAS  Google Scholar 

  22. Chumbalkar VC, Subhashini C, Dhople VM et al (2005) Differential protein expression in human gliomas and molecular insights. Proteomics 5:1167–1177. doi:10.1002/pmic.200401202

    Article  PubMed  CAS  Google Scholar 

  23. Tovi M, Hartman M, Lilja A et al (1994) MR imaging in cerebral gliomas. Tissue component analysis in correlation with histopathology of whole-brain specimens. Acta Radiol 35:495–505

    Article  PubMed  CAS  Google Scholar 

  24. Sugahara T, Korogi Y, Kochi M et al (1998) Correlation of MR imaging-determined cerebral blood volume maps with histologic and angiographic determination of vascularity of gliomas. AJR Am J Roentgenol 171:1479–1486

    PubMed  CAS  Google Scholar 

  25. Tynninen O, Aronen HJ, Ruhala M et al (1999) MRI enhancement and microvascular density in gliomas. Correlation with tumor cell proliferation. Invest Radiol 34:427–434. doi:10.1097/00004424-199906000-00007

    Article  PubMed  CAS  Google Scholar 

  26. Seliger B, Fedorushchenko A, Brenner W et al (2007) Ubiquitin COOH-terminal hydrolase 1: a biomarker of renal cell carcinoma associated with enhanced tumor cell proliferation and migration. Clin Cancer Res 13:27–37. doi:10.1158/1078-0432.CCR-06-0824

    Article  PubMed  CAS  Google Scholar 

  27. Wilkinson KD, Lee KM, Deshpande S et al (1989) The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246:670–673. doi:10.1126/science.2530630

    Article  PubMed  CAS  Google Scholar 

  28. Setsuie R, Wada K (2007) The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochem Int 51:105–111. doi:10.1016/j.neuint.2007.05.007

    Article  PubMed  CAS  Google Scholar 

  29. Hibi K, Liu Q, Beaudry GA et al (1998) Serial analysis of gene expression in non-small cell lung cancer. Cancer Res 58:5690–5694

    PubMed  CAS  Google Scholar 

  30. Campbell LK, Thomas JR, Lamps LW et al (2003) Protein gene product 9.5 (PGP 9.5) is not a specific marker of neural and nerve sheath tumors: an immunohistochemical study of 95 mesenchymal neoplasms. Mod Pathol 16:963–969. doi:10.1097/01.MP.0000087088.88280.B0

    Article  PubMed  Google Scholar 

  31. Hibi K, Kodera Y, Ito K et al (2004) Plasminogen activator inhibitor-1 is a downstream mediator of the PGP9.5-related oncogenic pathway in esophageal squamous cell carcinoma. Anticancer Res 24:3731–3734

    PubMed  CAS  Google Scholar 

  32. Takano T, Miyauchi A, Matsuzuka F et al (2004) PGP9.5 mRNA could contribute to the molecular-based diagnosis of medullary thyroid carcinoma. Eur J Cancer 40:614–618. doi:10.1016/j.ejca.2003.11.016

    Article  PubMed  CAS  Google Scholar 

  33. Sato N, Fukushima N, Maitra A et al (2003) Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 63:3735–3742

    PubMed  CAS  Google Scholar 

  34. Yamashita K, Park HL, Kim MS et al (2006) PGP9.5 methylation in diffuse-type gastric cancer. Cancer Res 66:3921–3927. doi:10.1158/0008-5472.CAN-05-1511

    Article  PubMed  CAS  Google Scholar 

  35. Lee YM, Lee JY, Kim MJ et al (2006) Hypomethylation of the protein gene product 9.5 promoter region in gallbladder cancer and its relationship with clinicopathological features. Cancer Sci 97:1205–1210. doi:10.1111/j.1349-7006.2006.00320.x

    Article  PubMed  CAS  Google Scholar 

  36. Yamazaki T, Hibi K, Takase T et al (2002) PGP9.5 as a marker for invasive colorectal cancer. Clin Cancer Res 8:192–195

    PubMed  CAS  Google Scholar 

  37. Tezel E, Hibi K, Nagasaka T et al (2000) PGP9.5 as a prognostic factor in pancreatic cancer. Clin Cancer Res 6:4764–4767

    PubMed  CAS  Google Scholar 

  38. al-Katib AM, Mohammad RM, Maki A et al (1995) Induced expression of a ubiquitin COOH-terminal hydrolase in acute lymphoblastic leukemia. Cell Growth Differ 6:211–217

    PubMed  CAS  Google Scholar 

  39. Brichory F, Beer D, Le Naour F et al (2001) Proteomics-based identification of protein gene product 9.5 as a tumor antigen that induces a humoral immune response in lung cancer. Cancer Res 61:7908–7912

    PubMed  CAS  Google Scholar 

  40. Takase T, Hibi K, Yamazaki T et al (2003) PGP9.5 overexpression in esophageal squamous cell carcinoma. Hepatogastroenterology 50:1278–1280

    PubMed  CAS  Google Scholar 

  41. Otsuki T, Yata K, Takata-Tomokuni A et al (2004) Expression of protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) in human myeloma cells. Br J Haematol 127:292–298. doi:10.1111/j.1365-2141.2004.05205.x

    Article  PubMed  CAS  Google Scholar 

  42. Bittencourt Rosas SL, Caballero OL, Dong SM et al (2001) Methylation status in the promoter region of the human PGP9.5 gene in cancer and normal tissues. Cancer Lett 170:73–79. doi:10.1016/S0304-3835(01)00449-9

    Article  PubMed  CAS  Google Scholar 

  43. Mandelker DL, Yamashita K, Tokumaru Y et al (2005) PGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. Cancer Res 65:4963–4968. doi:10.1158/0008-5472.CAN-04-3923

    Article  PubMed  CAS  Google Scholar 

  44. Shen H, Sikorska M, Leblanc J et al (2006) Oxidative stress regulated expression of ubiquitin carboxyl-terminal hydrolase-L1: role in cell survival. Apoptosis 11:1049–1059. doi:10.1007/s10495-006-6303-8

    Article  PubMed  CAS  Google Scholar 

  45. Ovaa H, Kessler BM, Rolen U et al (2004) Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci USA 101:2253–2258. doi:10.1073/pnas.0308411100

    Article  PubMed  CAS  Google Scholar 

  46. Gavioli R, Frisan T, Vertuani S et al (2001) c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol 3:283–288. doi:10.1038/35060076

    Article  PubMed  CAS  Google Scholar 

  47. Richardson SJ (2007) Cell and molecular biology of transthyretin and thyroid hormones. Int Rev Cytol 258:137–193. doi:10.1016/S0074-7696(07)58003-4

    Article  PubMed  CAS  Google Scholar 

  48. Kassem NA, Deane R, Segal MB et al (2006) Role of transthyretin in thyroxine transfer from cerebrospinal fluid to brain and choroid plexus. Am J Physiol Regul Integr Comp Physiol 291:R1310–R1315. doi:10.1152/ajpregu.00789.2005

    PubMed  CAS  Google Scholar 

  49. Palha JA, Nissanov J, Fernandes R et al (2002) Thyroid hormone distribution in the mouse brain: the role of transthyretin. Neuroscience 113:837–847. doi:10.1016/S0306-4522(02)00228-2

    Article  PubMed  CAS  Google Scholar 

  50. Albrecht S, Bayer TA, Kraus JA et al (1995) Transthyretin expression in medulloblastomas and medulloblastoma cell lines. Neuropathol Appl Neurobiol 21:399–409. doi:10.1111/j.1365-2990.1995.tb01077.x

    Article  PubMed  CAS  Google Scholar 

  51. Kunishio K, Shiraishi T, Mishima N et al (1991) Immunohistochemical study for choroid plexus papillomas and ependymomas. Neurol Med Chir (Tokyo) 31:859–866. doi:10.2176/nmc.31.859

    Article  CAS  Google Scholar 

  52. Zhang Z, Bast RC Jr, Yu Y et al (2004) Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64:5882–5890. doi:10.1158/0008-5472.CAN-04-0746

    Article  PubMed  CAS  Google Scholar 

  53. Fevre-Montange M, Hasselblatt M, Figarella-Branger D et al (2006) Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases. J Neuropathol Exp Neurol 65:1004–1011

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (R01-2008-000-20268-0) and the Seoul National University Hospital Research Fund (no. 04-2008-095).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital Cancer Research Institute, 28 Yeongeon-dong, Jongno-gu, Seoul, 110-744, Korea

    Chul-Kee Park, Ji Hye Jung, Hee-Won Jung & Byung-Kyu Cho

  2. Department of Pathology, Seoul National University College of Medicine, Seoul, 110-744, Korea

    Sung-Hye Park

Authors
  1. Chul-Kee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Hye Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung-Hye Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hee-Won Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Byung-Kyu Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chul-Kee Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, CK., Jung, J.H., Park, SH. et al. Multifarious proteomic signatures and regional heterogeneity in glioblastomas. J Neurooncol 94, 31–39 (2009). https://doi.org/10.1007/s11060-009-9805-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-009-9805-8

Keywords

Search

Navigation