Top

Published in:

Open Access 01-03-2011 | Clinical Study – Patient Study

Identification of diagnostic serum protein profiles of glioblastoma patients

Authors: Anja Elstner, Florian Stockhammer, Trong-Nghia Nguyen-Dobinsky, Quang Long Nguyen, Ingo Pilgermann, Amanjit Gill, Anke Guhr, Tingguo Zhang, Kajetan von Eckardstein, Thomas Picht, Julian Veelken, Robert L. Martuza, Andreas von Deimling, Andreas Kurtz

Published in: Journal of Neuro-Oncology | Issue 1/2011

Abstract

Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p < 0.0001, Fischer’s exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p < 0.0001, Fischer’s exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.

Sallinen SL, Sallinen PK, Haapasalo HK et al (2000) Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res 60(23):6617–6622PubMed

Rickman DS, Bobek MP, Misek DE et al (2001) Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res 61(18):6885–6891PubMed

Fuller GN, Hess KR, Rhee CH et al (2002) Molecular classification of human diffuse gliomas by multidimensional scaling analysis of gene expression profiles parallels morphology-based classification, correlates with survival, and reveals clinically-relevant novel glioma subsets. Brain Pathol 12(1):108–116CrossRefPubMed

Nutt CL, Mani DR, Betensky RA et al (2003) Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 63(7):1602–1607PubMed

Shai R, Shi T, Kremen TJ et al (2003) Gene expression profiling identifies molecular subtypes of gliomas. Oncogene 22(31):4918–4923CrossRefPubMed

van den Boom J, Wolter M, Kuick R et al (2003) Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163(3):1033–1043CrossRefPubMed

Liang Y, Diehn M, Watson N et al (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci USA 102(16):5814–5819CrossRefPubMed

Hess KR, Fuller GN, Rhee CH et al (2001) Statistical pattern analysis of gene expression profiles for glioblastoma tissues and cell lines. Int J Mol Med 8(2):183–188PubMed

Watson MA, Perry A, Budhraja V et al (2001) Gene expression profiling with oligonucleotide microarrays distinguishes World Health Organization grade of oligodendrogliomas. Cancer Res 61(5):1825–1829PubMed

10.

Reddy SP, Britto R, Vinnakota K et al (2008) Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis. Clin Cancer Res 14(10):2978–2987CrossRefPubMed

11.

Shirahata M, Iwao-Koizumi K, Saito S et al (2007) Gene expression-based molecular diagnostic system for malignant gliomas is superior to histological diagnosis. Clin Cancer Res 13(24):7341–7356CrossRefPubMed

12.

Furuta M, Weil RJ, Vortmeyer AO et al (2004) Protein patterns and proteins that identify subtypes of glioblastoma multiforme. Oncogene 23(40):6806–6814CrossRefPubMed

13.

Iwadate Y, Sakaida T, Hiwasa T et al (2004) Molecular classification and survival prediction in human gliomas based on proteome analysis. Cancer Res 64(7):2496–2501CrossRefPubMed

14.

Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476CrossRefPubMed

15.

Welsh JB, Sapinoso LM, Kern SG et al (2003) Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA 100(6):3410–3415CrossRefPubMed

16.

Diehn M, Eisen MB, Botstein D et al (2000) Large-scale identification of secreted and membrane-associated gene products using DNA microarrays. Nat Genet 25(1):58–62CrossRefPubMed

17.

Zhou W, Sokoll LJ, Bruzek DJ et al (1998) Identifying markers for pancreatic cancer by gene expression analysis. Cancer Epidemiol Biomarkers Prev 7(2):109–112PubMed

18.

Audero E, Cascone I, Zanon I et al (2001) Expression of angiopoietin-1 in human glioblastomas regulates tumor-induced angiogenesis: in vivo and in vitro studies. Arterioscler Thromb Vasc Biol 21(4):536–541PubMed

19.

Tanwar MK, Gilbert MR, Holland EC (2002) Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma. Cancer Res 62(15):4364–4368PubMed

20.

Streffer JR, Schuster M, Zipp F et al (1998) Soluble CD95 (Fas/APO-1) in malignant glioma: (no) implications for CD95-based immunotherapy? J Neurooncol 40(3):233–235CrossRefPubMed

21.

Krul ES, Tang J (1992) Secretion of apolipoprotein E by an astrocytoma cell line. J Neurosci Res 32(2):227–238CrossRefPubMed

22.

Koshikawa N, Nakamura T, Tsuchiya N et al (1996) Purification and identification of a novel and four known serine proteinase inhibitors secreted by human glioblastoma cells. J Biochem 119(2):334–339PubMed

23.

Roth W, Wild-Bode C, Platten M et al (2000) Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. Oncogene 19(37):4210–4220CrossRefPubMed

24.

Mishima K, Asai A, Kadomatsu K et al (1997) Increased expression of midkine during the progression of human astrocytomas. Neurosci Lett 233(1):29–32CrossRefPubMed

25.

Nano R, Capelli E, Argentina F et al (2003) Evaluation of serum levels of cytokines and intercellular adhesion molecule-1 (ICAM-1) in astrocytic tumours. Cell Mol Biol (Noisy-le-grand) 49(4):525–528

26.

Salmaggi A, Eoli M, Frigerio S et al (1999) Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and plasma thrombomodulin levels in glioblastoma patients. Cancer Lett 146(2):169–172CrossRefPubMed

27.

Koga K, Todaka T, Morioka M et al (2001) Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res 61(16):6248–6254PubMed

28.

Fayyad JA, Jahshan CS, Karam EG (2001) Systems development of child mental health services in developing countries. Child Adolesc Psychiatr Clin N Am 10(4):745–762 (ix)

29.

Kavsan V, Shostak K, Dmitrenko V et al (2005) Characterization of genes with increased expression in human glioblastomas. Tsitol Genet 39(6):37–49PubMed

30.

Freije WA, Castro-Vargas FE, Fang Z et al (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64(18):6503–6510CrossRefPubMed

31.

Ehtesham M, Yuan X, Kabos P et al (2004) Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6(3):287–293CrossRefPubMed

32.

Kim JH, Skates SJ, Uede T et al (2002) Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 287(13):1671–1679CrossRefPubMed

33.

Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847CrossRefPubMed

34.

Webb G, Zhang S (2002) Beyond association rules: generalized rule discovery. Kluwer, Dordrecht

35.

Webb G (1995) OPUS: an efficient admissible algorithm for unordered search. J Artif Intell Res 3:431–465

36.

Doddi S, Marathe A, Ravi SS et al (2001) Discovery of association rules in medical data. Med Inform Internet Med 26(1):25–33CrossRefPubMed

37.

Davidson AC, Hinkley DV (1997) Bootstrap methods and their application. Cambridge University Press, Cambridge

38.

Johann DJ Jr, McGuigan MD, Patel AR et al (2004) Clinical proteomics and biomarker discovery. Ann N Y Acad Sci 1022:295–305

39.

Bucca G, Carruba G, Saetta A et al (2004) Gene expression profiling of human cancers. Ann N Y Acad Sci 1028:28–37

40.

Naylor DJ, Hartl FU (2001) Contribution of molecular chaperones to protein folding in the cytoplasm of prokaryotic and eukaryotic cells. Biochem Soc Symp 68:45–68

41.

Kurtz A, Zimmer A, Schnutgen F et al (1994) The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. Development 120(9):2637–2649PubMed

42.

Pockley AG, Georgiades A, Thulin T et al (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42(3):235–238CrossRefPubMed

43.

Chan CP, Sanderson JE, Glatz JF et al (2004) A superior early myocardial infarction marker. Human heart-type fatty acid-binding protein. Z Kardiol 93(5):388–397CrossRefPubMed

44.

Chan KC, Lucas DA, Hise D et al (2004) Analysis of the human serum proteome. Clin Proteom 1(2):26CrossRef

45.

Adler MW, Rogers TJ (2005) Are chemokines the third major system in the brain? J Leukoc Biol 78(6):1204–1209CrossRefPubMed

46.

Angiolillo AL, Sgadari C, Taub DD et al (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182(1):155–162CrossRefPubMed

47.

Strik HM, Weller M, Frank B et al (2000) Heat shock protein expression in human gliomas. Anticancer Res 20(6B):4457–4462PubMed

48.

Zhong L, Peng X, Hidalgo GE et al (2003) Antibodies to HSP70 and HSP90 in serum in non-small cell lung cancer patients. Cancer Detect Prev 27(4):285–290CrossRefPubMed

49.

Chattopadhyay N, TFH J, Godbole MM et al (2004) Transforming growth factor beta receptor family ligands inhibit hepatocyte growth factor synthesis and secretion from astrocytoma cells. Brain Res Mol Brain Res 121(1–2):146–150CrossRefPubMed

50.

Hallahan AR, Pritchard JI, Chandraratna RA et al (2003) BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 9(8):1033–1038CrossRefPubMed

51.

Yang S, Pham LK, Liao CP et al (2008) A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. Cancer Res 68(1):198–205CrossRefPubMed

52.

Landry Y, Gies JP (2008) Drugs and their molecular targets: an updated overview. Fundam Clin Pharmacol 22(1):1–18CrossRefPubMed

53.

Brem S, Tsanaclis AM, Gately S et al (1992) Immunolocalization of basic fibroblast growth factor to the microvasculature of human brain tumors. Cancer 70(11):2673–2680CrossRefPubMed

54.

Dudek AZ, Mahaseth H (2005) Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Cancer Invest 23(3):193–200CrossRefPubMed

55.

Brat DJ, Kaur B, Van Meir EG (2003) Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors. Front Biosci 8:d100–d116

56.

Shen L, Dean NM, Glazer RI (1999) Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Calpha antisense oligonucleotide. Mol Pharmacol 55(2):396–402PubMed

Title: Identification of diagnostic serum protein profiles of glioblastoma patients
Authors: Anja Elstner
Florian Stockhammer
Trong-Nghia Nguyen-Dobinsky
Quang Long Nguyen
Ingo Pilgermann
Amanjit Gill
Anke Guhr
Tingguo Zhang
Kajetan von Eckardstein
Thomas Picht
Julian Veelken
Robert L. Martuza
Andreas von Deimling
Andreas Kurtz
Publication date: 01-03-2011
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 1/2011
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-010-0284-8

At a glance: The STEP trials

Springer Medicine

Identification of diagnostic serum protein profiles of glioblastoma patients

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2011

Pseudoprogression in patients with malignant gliomas treated with concurrent temozolomide and radiotherapy: potential role of p53

A prospective study of nonfunctioning pituitary adenomas: presentation, management, and clinical outcome

Helianthin induces antiproliferative effect on human glioblastoma cells in vitro

Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience

Low-level copy number changes of MYC genes have a prognostic impact in medulloblastoma

Coexisting cranial and multiple spinal meningioma in a child-report of a case