Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone

Abstract

Current therapies for glioblastoma (GBM) target bulk tumor through measures such as resection and radiotherapy. However, recent evidence suggests that targeting a subset of tumor cells, so-called cancer stem cells, may be critical for inhibiting tumor growth and relapse. The subventricular zone (SVZ), which lines the ventricles of the brain, is thought to be the origin for the majority of neural stem cells and potentially cancer stem cells. Therefore, we assessed the relationship between tumor contact with the SVZ as determined by MRI, cancer stem cell gene expression and survival in 47 patients with GBM. Using DNA microarrays, we found that genes associated with cancer stem cells were not over-expressed in tumors contacting the SVZ. Contact with the SVZ trended with shorter survival (median 358 versus 644, P = 0.066). Over-expression of CD133 (prominin-1) and maternal embryonic leucine zipper kinase (MELK) was associated with shorter survival, whereas mitogen activated protein kinase 8 (MAPK8) was associated with longer survival (P values 0.008, 0.005 and 0.002 respectively). Thus we found no evidence of a stem-cell derived genetic signature specific for GBM in contact with the SVZ, but there was a relationship between stem cell gene expression and survival. More research is required to clarify the relationship between the SVZ, cancer stem cells and survival.

Fig. 1

Tumor grading. Group I (a), tumor contacting SVZ and infiltrating cortex (n = 13); group II (b), tumor contacting SVZ but not involving the cortex (n = 12); group III (c), tumor involving cortex but not contacting the SVZ (n = 16); group IV (d), tumor involving neither SVZ nor cortex (n = 6)

Fig. 2

Heat map of stem cell probes across group I–IV. Red corresponds to higher gene expression levels. Patient samples noted along top row

Fig. 3

Heat map of differentially expressed genes between group II tumors versus the remainders. Note that several immune related genes (blue) show higher expression in group 2 tumors. Red corresponds to higher gene expression levels

Fig. 4

Kaplan–Meier curves of group II versus groups I, III and IV combined (a) and Kaplan–Meier curves of group I and II combined versus groups III and IV combined (b)

Fig. 5

Kaplan–Meier curves for selected genes: a MAPK8, b CD133, c BMP-4, d MELK, e CARM1 and f LOXL2. For all graphs the dashed line indicates survival data for patients with greater than median gene expression levels, and the solid line is for patients with less than median gene expression levels. Note that increased levels of MAPK and BMP-4 expression are associated with longer survival, whereas increased CD133 and MELK expression levels correlate with shorter survival. Increased CARM1 and LOXL2 (enriched in SVZ-contacting tumors) also are correlated with poorer survival