Skip to main content

Advertisement

Log in

Exploratory investigation of eight circulating plasma markers in brain tumor patients

  • Original Article
  • Published:
Neurosurgical Review Aims and scope Submit manuscript

Abstract

Several blood biomarkers have been established for the early diagnosis, screening and follow-up of non central nervous system cancers. However, there is lack of knowledge on biochemical blood alterations in brain tumor patients. In this study, we prospectively collected blood plasma samples of 105 adult brain tumor patients with diffuse low-grade glioma (World Health Organization (WHO) II, n = 7), anaplastic glioma (WHO III, n = 10), glioblastoma multiforme (WHO IV, glioblastoma multiforme (GBM)) (n = 34), meningioma (WHO I, n = 8), atypical meningioma (WHO II, n = 5), and intracerebral metastasis (ICM; n = 41). In each case, we measured plasma concentrations of neuropeptide Y, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, placental growth factor (PlGF), S100B, secretagogin, interleukin 8, and glial fibrillary acidic protein (GFAP) using enzyme-linked immunosorbent assay. Plasma marker concentrations were correlated to patient parameters including neuropathological diagnosis and neuroradiological features. Most of the markers were detectable in all diagnostic categories in variable concentrations. GFAP plasma detectability was strongly associated with a diagnosis of GBM (p < 0.001). Plasma GFAP and plasma placental growth factor showed promising moderate potential in the differential diagnosis of unifocal GBM versus unifocal supratentorial ICM (area under the curve = 0.73, p < 0.05). To summarize, our data show that none of the investigated markers is suitable to substitute histological diagnosis. However, measurement of circulating GFAP and PlGF may support neuroradiological differential diagnosis of GBM versus ICM.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Attems J, Preusser M, Grosinger-Quass M, Wagner L, Lintner F, Jellinger K (2008) Calcium-binding protein secretagogin-expressing neurones in the human hippocampus are largely resistant to neurodegeneration in Alzheimer's disease. Neuropathol Appl Neurobiol 34:23–32

    PubMed  CAS  Google Scholar 

  2. Azad NS, Annunziata CM, Steinberg SM, Minasian L, Premkumar A, Chow C, Kotz HL, Kohn EC (2008) Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy. Cancer 112:1726–1732

    Article  PubMed  CAS  Google Scholar 

  3. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28:2817–2823

    Article  PubMed  CAS  Google Scholar 

  4. Benarroch EE (2009) Neuropeptide Y: its multiple effects in the CNS and potential clinical significance. Neurology 72:1016–1020

    Article  PubMed  Google Scholar 

  5. Bender R, Lange S (2001) Adjusting for multiple testing—when and how? J Clin Epidemiol 54:343–349

    Article  PubMed  CAS  Google Scholar 

  6. Berglund A, Molin D, Larsson A, Einarsson R, Glimelius B (2002) Tumour markers as early predictors of response to chemotherapy in advanced colorectal carcinoma. Ann Oncol 13:1430–1437

    Article  PubMed  CAS  Google Scholar 

  7. Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7:122–133

    Article  PubMed  CAS  Google Scholar 

  8. Brochez L, Naeyaert JM (2000) Serological markers for melanoma. Br J Dermatol 143:256–268

    Article  PubMed  CAS  Google Scholar 

  9. Brommeland T, Rosengren L, Fridlund S, Hennig R, Isaksen V (2007) Serum levels of glial fibrillary acidic protein correlate to tumour volume of high-grade gliomas. Acta Neurol Scand 116:380–384

    Article  PubMed  CAS  Google Scholar 

  10. Christensen JG, Vincent PW, Klohs WD, Fry DW, Leopold WR, Elliott WL (2005) Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor. Mol Cancer Ther 4:938–947

    Article  PubMed  CAS  Google Scholar 

  11. Ekblad E, Edvinsson L, Wahlestedt C, Uddman R, Hakanson R, Sundler F (1984) Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul Pept 8:225–235

    Article  PubMed  CAS  Google Scholar 

  12. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451

    Article  PubMed  CAS  Google Scholar 

  13. Englund AT, Geffner ME, Nagel RA, Lippe BM, Braunstein GD (1991) Pediatric germ cell and human chorionic gonadotropin-producing tumors. Clinical and laboratory features. Am J Dis Child 145:1294–1297

    PubMed  CAS  Google Scholar 

  14. Frota ER, Rodrigues DH, Donadi EA, Brum DG, Maciel DR, Teixeira AL (2009) Increased plasma levels of brain derived neurotrophic factor (BDNF) after multiple sclerosis relapse. Neurosci Lett 460:130–132

    Article  PubMed  CAS  Google Scholar 

  15. Gartner W, Ilhan A, Neziri D, Base W, Weissel M, Wohrer A, Heinzl H, Waldhor T, Wagner L, Preusser M (2010) Elevated blood markers 1 year before manifestation of malignant glioma. Neuro Oncol 12:1004–1008

    Article  PubMed  CAS  Google Scholar 

  16. Gartner W, Lang W, Leutmetzer F, Domanovits H, Waldhausl W, Wagner L (2001) Cerebral expression and serum detectability of secretagogin, a recently cloned EF-hand Ca(2+)-binding protein. Cereb Cortex 11:1161–1169

    Article  PubMed  CAS  Google Scholar 

  17. Hamaya K, Doi K, Tanaka T, Nishimoto A (1985) The determination of glial fibrillary acidic protein for the diagnosis and histogenetic study of central nervous system tumors: a study of 152 cases. Acta Med Okayama 39:453–462

    PubMed  CAS  Google Scholar 

  18. Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K (1994) Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol 56:559–564

    PubMed  CAS  Google Scholar 

  19. Harrell FE Jr, Lee KL, Mark DB (1996) Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 15:361–387

    Article  PubMed  Google Scholar 

  20. Hosmer DW, Lemeshow S (2000) Applied logistic regression. Wiley, New York

    Book  Google Scholar 

  21. Hu Y, Wang YD, Guo T, Wei WN, Sun CY, Zhang L, Huang J (2007) Identification of brain-derived neurotrophic factor as a novel angiogenic protein in multiple myeloma. Cancer Genet Cytogenet 178:1–10

    Article  PubMed  CAS  Google Scholar 

  22. Ilyin SE, Gayle D, Gonzalez-Gomez I, Miele ME, Plata-Salaman CR (1999) Brain tumor development in rats is associated with changes in central nervous system cytokine and neuropeptide systems. Brain Res Bull 48:363–373

    Article  PubMed  CAS  Google Scholar 

  23. Jacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA (1978) Determination of glial fibrillary acidic protein (GFAP) in human brain tumors. J Neurol Sci 35:147–155

    Article  PubMed  CAS  Google Scholar 

  24. Jung CS, Foerch C, Schanzer A, Heck A, Plate KH, Seifert V, Steinmetz H, Raabe A, Sitzer M (2007) Serum GFAP is a diagnostic marker for glioblastoma multiforme. Brain 130:3336–3341

    Article  PubMed  CAS  Google Scholar 

  25. Korner M, Reubi JC (2008) Neuropeptide Y receptors in primary human brain tumors: overexpression in high-grade tumors. J Neuropathol Exp Neurol 67:741–749

    Article  PubMed  CAS  Google Scholar 

  26. Kos K, Harte AL, James S, Snead DR, O'Hare JP, McTernan PG, Kumar S (2007) Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass. Am J Physiol Endocrinol Metab 293:E1335–1340

    Article  PubMed  CAS  Google Scholar 

  27. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J (1996) The ABCs of measuring intracerebral hemorrhage volumes. Stroke 27:1304–1305

    Article  PubMed  CAS  Google Scholar 

  28. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    Article  PubMed  CAS  Google Scholar 

  29. Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69:94–103

    Article  PubMed  CAS  Google Scholar 

  30. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132

    Article  PubMed  CAS  Google Scholar 

  31. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. IARC, Lyon

    Google Scholar 

  32. Mariani L, Miceli R, Michilin S, Gion M (2009) Serial determination of CEA and CA 15.3 in breast cancer follow-up: an assessment of their diagnostic accuracy for the detection of tumour recurrences. Biomarkers 14:130–136

    Article  PubMed  CAS  Google Scholar 

  33. McDavid K, Lee J, Fulton JP, Tonita J, Thompson TD (2004) Prostate cancer incidence and mortality rates and trends in the United States and Canada. Public Health Rep 119:174–186

    PubMed  Google Scholar 

  34. Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H (1998) Placenta growth factor (PlGF) mRNA expression in brain tumors. J Neurooncol 40:123–130

    Article  PubMed  CAS  Google Scholar 

  35. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500

    Article  PubMed  CAS  Google Scholar 

  36. Pipp I, Wagner L, Rossler K, Budka H, Preusser M (2007) Secretagogin expression in tumours of the human brain and its coverings. APMIS 115:319–326

    Article  PubMed  CAS  Google Scholar 

  37. Przedborski S, Goldman S, Schiffmann SN, Vierendeels G, Depierreux M, Levivier M, Hildebrand J, Vanderhaeghen JJ (1988) Neuropeptide Y, somatostatin, and cholecystokinin neurone preservation in anaplastic astrocytomas. Acta Neuropathol 76:507–510

    Article  PubMed  CAS  Google Scholar 

  38. Rickmann M, Wolff JR (1995) Modifications of S100-protein immunoreactivity in rat brain induced by tissue preparation. Histochem Cell Biol 103:135–145

    Article  PubMed  CAS  Google Scholar 

  39. Saavedra A, Baltazar G, Duarte EP (2008) Driving GDNF expression: the green and the red traffic lights. Prog Neurobiol 86:186–215

    Article  PubMed  CAS  Google Scholar 

  40. Straten G, Eschweiler GW, Maetzler W, Laske C, Leyhe T (2009) Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls. J Alzheimers Dis 18:331–337

    PubMed  CAS  Google Scholar 

  41. Tjwa M, Luttun A, Autiero M, Carmeliet P (2003) VEGF and PlGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res 314:5–14

    Article  PubMed  CAS  Google Scholar 

  42. Vogelbaum MA, Masaryk T, Mazzone P, Mekhail T, Fazio V, McCartney S, Marchi N, Kanner A, Janigro D (2005) S100beta as a predictor of brain metastases: brain versus cerebrovascular damage. Cancer 104:817–824

    Article  PubMed  CAS  Google Scholar 

  43. Wagner L, Oliyarnyk O, Gartner W, Nowotny P, Groeger M, Kaserer K, Waldhausl W, Pasternack MS (2000) Cloning and expression of secretagogin, a novel neuroendocrine- and pancreatic islet of Langerhans-specific Ca2+-binding protein. J Biol Chem 275:24740–24751

    Article  PubMed  CAS  Google Scholar 

  44. Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H, Humpel C (2000) Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol 99:131–137

    Article  PubMed  CAS  Google Scholar 

  45. Wohrer A, Waldhor T, Heinzl H, Hackl M, Feichtinger J, Gruber-Mosenbacher U, Kiefer A, Maier H, Motz R, Reiner-Concin A, Richling B, Idriceanu C, Scarpatetti M, Sedivy R, Bankl HC, Stiglbauer W, Preusser M, Rossler K, Hainfellner JA (2009) The Austrian Brain Tumour Registry: a cooperative way to establish a population-based brain tumour registry. J Neurooncol 95:401–411

    Article  PubMed  Google Scholar 

  46. Yamamoto H, Gurney ME (1990) Human platelets contain brain-derived neurotrophic factor. J Neurosci 10:3469–3478

    PubMed  CAS  Google Scholar 

  47. Yan Q, Yu HL, Li JT (2009) Study on the expression of BDNF in human gliomas. Sichuan Da Xue Xue Bao Yi Xue Ban 40:415–417

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Anniversary Fund (Jubilaeumsfonds) of the Austrian National Bank, project number: 13402.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthias Preusser.

Additional information

Comment

Benedicto Oscar Colli, Ribeirão Preto, Brasil

I would like to congratulate the authors for this interesting work on tumor biology. Identification of biological markers in the blood associated with tumors probably will be the key for precocious detection of tumors and, we hope, even before the tumor starts to develop and this paper is a practical evidence of the utility of molecular biology. Using imunohistochemistry detection of some biological markers in the blood, the authors intended to associate these markers with primary and secondary tumors of the central nervous system, a topic not so much explored in the literature.

The authors appropriately comment the weak points of the study, emphasizing the small sample number for some tumors (low-grade gliomas and meningiomas) and the lack of histopathological diagnosis for most part (62.3 %) of patients with supposed brain metastasis that precluded stronger conclusions. Besides of this, only one marker was analyzed in the control group and in the group with multiple sclerosis due the small amount volume of the samples. Another problem was a technical limitation due to the fact that commercial kits for plasma analysis measures only the concentrations which are above the level of detection givens for each assay and, therefore, the measures were done according to their detectability (detectable vs. nondetectable), which causes loss of information.

Their results were submitted to very meticulous and sophisticated statistical analysis that allowed confidence on the results.

The main conclusion was that presence of GFAP (glial fibrillary acidi protein) in the plasma was more frequent in patients with glioblastoma multiforme and PlGF (placental growth factor) was more frequent in patients with brain metastasis and this can help in the differentiation of these tumors before histopathological analysis.

Additionally, it was also suggested, without statistical significance, that patients with glioblastoma and with GFAP detected in the plasma has better survival than patients that had not GFAP detected in the plasma. It was also noted inverses association of plasma–NPY concentrations with tumor grade for gliomas and meningiomas, an inverse association of IL8 plasma concentration with tumor grade in gliomas, and a positive association of plasma–PlGF concentrations with tumor grade in meningiomas.

The results of this study are promising and if confirmed and more explored with adequate samples of tumors, they can be a valuable contribution for diagnosis and prognosis of tumors of the central nervous system.

Tamas Doczi, Pecs, Hungary

Conventional structural imaging provides limited information on tumor characterization and prognosis. Advances in neurosurgical techniques, radiotherapy planning and novel drug treatments for malignant brain tumors have generated increasing need for reproducible, noninvasive, quantitative imaging biomarkers such as physiological MRI and PET molecular imaging that help in understanding metabolic processes associated with tumor growth, blood flow and fine structure. Despite their added value, the effect of these imaging biomarkers as an adjunct to structural imaging in clinical research and practice have remained rather limited. Searching for systemic biomarkers of intracerebral pathologies is also of major interest. Blood markers for CNS tumors, if identified, would be of great value for allowing differential diagnosis without obtaining tissue and for diagnosing recurrences of CNS tumors. This latter would be of considerable value especially in the case of malignant gliomas where pseudo-progression is a common clinical problem. The authors investigated at 8 of traditional and some novel candidate plasma markers. Their present results and conclusions are limited by the small number of probands. The study in the present form does not help the reader to get a definite answer to the question, are molecular biomarkers in neuro-oncology ready for clinical practice? The study presents tendencies rather than definite differences, with the exception of the authors’ (non-novel) observation of higher GFAP levels in GBM patients than in metastasis patients.

However, this prospective exploratory study investigating the blood plasma concentrations of several distinct proteins and their association with cerebral tumor type and neuroradiological features in adult brain tumor patients may help neurosurgeons to get acquainted with potential areas for which biomarkers can improve patient care. It may range from early detection and diagnosis, prediction of response or toxicity of therapy and prognosis. Blood markers can also potentially improve the efficiency of the development of novel treatment approaches.

James T Rutka, Toronto, Canada

The authors have examined the role of plasma biomarkers in 105 adult brain tumor patients who had a variety of different tumor types. They chose, a priori, 8 different biomarkers that were selected on the basis of their known involvement in processes that affect the growth of cells within the central nervous system. The concentrations of these biomarkers were correlated with clinicopathological data. In the end, they show that GFAP was a strongly associated biomarker with GBM, and GFAP and PlGF were promising in differentiating between GBM and unifocal supratentorial metastasis.

This is an important study because any attempt at establishing a diagnosis of an intracranial brain tumor by minimally invasive strategies, such as a blood marker, would be extremely valuable. A lot of energy and effort now are being directed at establishing such biomarkers in a host of different cancer types. Ideally, we would like to see the sensitivity and specificity of a biomarker that is wholly diagnostic and prognostic such as is the case with certain intracranial germ cell tumors that express alpha fetoprotein, or human chorionic gonadotropin to give some examples.

As the field of proteomics expands, and as the detection of rare proteins at low concentrations becomes possible, we can look forward to the establishment of unique biomarkers for various brain tumors which have hitherto gone undetected. I congratulate the authors for this interesting body of work.

Walter Stummer, Münster, Germany

This is an analysis of potential blood markers for CNS tumors. Such blood markers, if identified, would be of great value for allowing differential diagnosis without obtaining tissue and for diagnosing recurrences of CNS tumors. The latter would be of considerable value especially in the case of malignant gliomas where phenomena as pseudo-progression or pseudo-response are a common clinical problem. The authors investigate a number of traditional and some novel candidate plasma markers.

However, the results and conclusions are limited by the small number of patients and require careful scrutiny, with the exception of the authors’ (non-novel) observation of higher GFAP levels in GBM patients than in those with metastastic tumors. To be more convincing, this dataset needs to be validated in an independent sample or, in a first step, should be expanded to a larger group of patients. It would be of particular interest to test the markers in recurrent glioblastomas. In my experience these tumors pose much more of a formidable clinical problem than discerning a malignant glioma from a metastasis.

Enver Bogdanov and A. Zabbarova, Kazan, Russia

Ilhan-Mutlu A., Preusser M. and co-authors present the results of the research of eight circulation plasma markers in brain tumor patients. In the panel of investigated proteins authors used six known and 2 new for the neurooncological patients’ substances. Results of this study indicate that 2 proteins (GFAP and PIGF) are potentially useful as clinical biomarkers that may support neuroradiological differential diagnosis of glioblastoma multiforme versus intracerebral metastasis. None of the markers investigated in this study showed the potential to replace histological diagnosis.

This research is based on sufficient clinical material and references and is of big practical interest. At the same time, as noted by the authors themselves, this study requires further. The search for new markers, a comparison of markers in plasma and in CSF, the expansion of the number of patients enrolled in the study and analysis of their neurological status and outcomes is an important for the screening, early diagnosis and prognosis of the patients, as well as to clarify the classification of brain tumors and to identify possible paraneoplastic syndroms.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

ESM 1

Plasma marker detectability according to tumor type and neuroradiological parameters. Statistically significant group differences are highlighted (gray background; p < 0.05, tumor volume was assessed using Mann–Whitney U test, all other variables were analyzed using chi-square test). BDNF brain-derived neurotrophic factor, GDNF glial cell line-derived neurotrophic factor, GFAP glial fibrillary acidic protein, IL8 interleukin 8, M median, NPY neuropeptide Y, R range (calculated at least from two positive values), PlGF placental growth factor, SCGN secretagogin. Tumor volume is demonstrated in median with minimum and maximum (XLS 36 kb)

ESM 2

Plasma marker detectability according to tumor type and anatomical localization. There was no statistically significant association of plasma marker detectability with tumor localization (all p > 0.05, logistic regression). Tumor volume is demonstrated in median with minimum and maximum and was assessed using Kruskal–Wallis test. BDNF brain-derived neurotrophic factor, GDNF glial cell line-derived neurotrophic factor, GFAP glial fibrillary acidic protein, IL8 interleukin 8, NPY neuropeptide Y, PlGF placental growth factor, SCGN secretagogin (XLS 22 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ilhan-Mutlu, A., Wagner, L., Widhalm, G. et al. Exploratory investigation of eight circulating plasma markers in brain tumor patients. Neurosurg Rev 36, 45–56 (2013). https://doi.org/10.1007/s10143-012-0401-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10143-012-0401-6

Keywords

Navigation