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High levels of c-Met is associated with poor prognosis in glioblastoma

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Abstract

The tyrosine kinase receptor c-Met has been suggested to be involved in crucial parts of glioma biology like tumor stemness, growth and invasion. The aim of this study was to investigate the prognostic value of c-Met in a population-based glioma patient cohort. Tissue samples from 238 patients with WHO grade I, II, III and IV tumors were analyzed using immunohistochemical staining and advanced image analysis. Strong c-Met expression was found in tumor cells, blood vessels, and peri-necrotic areas. At the subcellular level, c-Met was identified in the cytoplasm and in the cell membrane. Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0.03). However the prognostic effect of c-Met in glioblastomas was time-dependent and only observed in patients who survived more than 8.5 months, and not within the first 8.5 months after diagnosis. This was significant in multivariate analysis (HR 1.99, 95 % CI 1.29–3.08, p = 0.002) adjusted for treatment and the clinical variables age (HR 1.01, 95 % CI 0.99–1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17–1.53, p < 0.001), and tumor crossing midline (HR 1.28, 95 % CI 0.79–2.07, p = 0.29). In conclusion, this study showed that high levels of c-Met holds unfavorable prognostic value in glioblastomas.

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Acknowledgments

We acknowledge the excellent laboratory work by the technicians Helle Wohlleben and Tanja Dreehsen Højgaard. This work was supported by the Cancer Foundation, the Carl J. Becker’s Foundation, the Jacob and Olga Madsen Foundation, the Danish Cancer Research Foundation, the Karen A. Tolstrup Foundation, and the Beckett Foundation.

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Authors and Affiliations

  1. Department of Pathology, Odense University Hospital, Winsløwparken 15, 3 Floor, 5000, Odense C, Denmark

    Stine Asferg Petterson, Simon Kjær Hermansen, Sune K. A. Munthe, Michael Tveden Gundesen, Helle Wohlleben, Tine Rasmussen & Bjarne Winther Kristensen

  2. Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, 5000, Odense C, Denmark

    Simon Kjær Hermansen, Sune K. A. Munthe, Michael Tveden Gundesen, Christoph Patrick Beier, Steinbjørn Hansen & Bjarne Winther Kristensen

  3. Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Rikke Hedegaard Dahlrot & Steinbjørn Hansen

  4. Department of Neurosurgery, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Sune K. A. Munthe

  5. Department of Neurology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Tine Rasmussen & Christoph Patrick Beier

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11060_2015_1723_MOESM1_ESM.tif

C-Met intensity levels in ten GBMs. No significant differences between intensities were obtained by sampling 5, 10, 15 or 20 % of the tumor area. However sampling 5 % of the tumor tissue did not provide at least five usable pictures in small tumors, and sampling 15 or 20 % of the tumor tissue was time consuming. Consequently, sampling of 10 % of the tumor tissue was chosen for the whole cohort. The data are shown as mean with SEM.

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Petterson, S.A., Dahlrot, R.H., Hermansen, S.K. et al. High levels of c-Met is associated with poor prognosis in glioblastoma. J Neurooncol 122, 517–527 (2015). https://doi.org/10.1007/s11060-015-1723-3

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