Dr John Greenman Research

Investigation of the functions of Vascular Endothelial Growth Factor-A and Interleukin-10 in low and high-grade brain tumours, and the potential of these factors as prognostic markers

Principal Investigators: Dr John Greenman, Reader in Tumour Immunology, Postgraduate Medical Institute, University of Hull and Mr David O’Brien, Consultant Neurosurgeon and Honorary Senior Lecturer, Hull Royal Infirmary.

Roles of VEGF-A & IL-10

Summary of Research in Layman’s terms

We investigated the association between 2 chemical messengers in patients with brain tumours. These chemical messengers are Vascular Endothelial Growth Factor-A or VEGF-A and Interelukin-10 (IL-10). Preliminary work has shown that the amount of these molecules appears to increase with tumour grade. The number of microglia cells in the tumour also increases with tumour grade. Both tumour cells and microglia are known to produce both VEGF-A and IL10.

Microglia play an important role in controlling how the immune system responds to tumours and the number of these cells is proportionate to the amount of IL-10 produced. Interestingly these cells also express receptors for VEGF-A. We hypothesize that VEGF-A may be critically important in stimulating microglia cells to produce IL-10, which in turn will affect how well the immune system can react against the tumour.

In order to try and prove our hypothesis, we have designed a three-part study.

1. Patient study
All patients with newly diagnosed brain tumours were invited to join the study whereby serum samples are given for cytokine analysis. We recruited over 150 patients and have analysed the serum from 90 of these. Circulating levels of VEGF appears to increase as the tumour becomes more aggressive. Serum IL-10 however was only detectable in approximately half the patients. We also analysed 10 brain tumour cyst fluids for these cytokines and they all are significantly elevated compared with their matched serum levels. Cyst VEGF levels were elevated over a thousand fold compared with serum. Further analyses will be preformed to investigate any associations between the cytokines in serum and cyst fluid. Analyses will also be performed to see if these factors can be used predictively in terms of patient survival.

2. Immunohistochemistry
Patient tumour samples were stained for the presence of VEGF-A and IL10 receptors. We correlated the changes of these cytokines and the receptors with tumour grade and the levels of circulating cytokines. Once again the expression patterns of staining were correlated with survival to see if there is any prognostic value.

3. Cell culture model focused on low grade brain tumours
We planned to establish an in vitro model using astrocytoma cell lines to analyse the cytokine repertoire that brain tumours produce and the cytokine receptors they possess on their surface. Once the receptor status has been established, appropriate cytokines, (e.g. IL10 and VEGF), will be added and the production of cytokines released in response will be determined. It is hoped that this model will provide an understanding of the relationship(s) between key cytokines involved in tumour development.

First Year Report Highlights (Feb2007)

Patient recruitment continued and we currently have a total of 239 serum samples from patients with primary tumours. Within this cohort there are 31 meningiomas; 23 mixed low-grade tumours, 71 GBMs and 38 metastatic samples. In addition we have stored serum from 66 age and sex-matched non-cancer controls.

Analysis so far has showed a statistically significant imbalance with both the Th2 cytokines (IL-4, IL-10) being higher in the GBM cohort (manuscript in preparation).
Analysis of prognostic value has begun for the patients with at least 12 months follow-up and will be continued over the next year.

Immunohistochemical staining for VEGF and its associated receptors is in progress. Serum and staining data will be examined as independent prognostic factors.

Presentations given in support of this work:

Systemic Immune Modulation in GBM
HYMS, Hull 2006

Cytokine Imbalance in GBM
Freyers, Galway, 31st Sept 2006
Kamdar.D.J.et al Irish Jounal of Medical Science
175:(3) 70

Cytokine Imbalance in GBM. A primary tumour effect? or secondary to steroid use?
SBNS, Lake District, Sept.2006
Kamdar.D.J.et al Br.J.Neurosurgery

Systemic Immune Dysfunction in GBM
EFNS, Glasgow, Sept.4th 2006
Kamdar.D.J.et al Poster Eur.J.of Neurol (13) Supplement 2, 273

Immune Imbalance in GBM
BNOS June 2006
Kamdar.D.J. Poster

Systemic Immune Imbalance in GBM
BNRG, Haywards Heath, March 2006
Kamdar.D.J.

TH1/TH2 Cytokine Imbalance in GBM
30th Freyers, Galaway, Sept.2005
Kamdar.D.J. et al (2005).Irish Journal of Medical Science 174 (3) 89

Systemic Immuno-modulation in GBM
Presented at SBNS, Torquay Sept.2005

ALTERATION IN THE TH1 AND TH2 CYTOKINE PROFILE IN PATIENTS WITH BRAIN TUMOURS
Poster presentation at SBNS, Manchester on 23rd September 2004
Poster presentation at 7th International Congress of Neuroimmunology, Venice on 1st October 2004
Poster presentation at Annual Meeting of BNOS, Wolverhampton on 25th June 2004

DOES A RELATIONSHIP EXIST BETWEEN SERUM AND CYST VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND INTERLEUKIN-10 (IL-10) IN PATIENTS WITH BRAIN TUMOURS?
Oral presentation at Annual Meeting of British Neuro-Oncology Society (BNOS), Wolverhampton on 25th June 2004

A STUDY OF INTRACAVITARY CYTOKINE LEVELS IN BRAIN TUMOURS
Oral & poster presentation at Meeting of British Neurological Research Group (BNRG), Hull on 4th March 2004
Poster presentation at Annual Congress of British Society of Immunology (BSI), Harrogate International Centre on 2nd December 2003

THE ASSOCIATION OF SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND INTERLEUKIN-10 (IL-10) IN BRAIN TUMOURS
Oral presentation at Meeting of Society of British Neurological Surgeons (SBNS), Cardiff on 19th September 2003

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