It has been hypothesized that gliomas arise from stem cells originating in the SVZ. Previously it has been reported that more aggressive patterns of GBM recurrence are associated with tumors that contact the SVZ, and that these tumors may express a “stem-cell-derived” phenotype that could impact treatment decisions [9
]. Therefore we analyzed the relationship between expression of cancer stem-cell genes, contact of tumor with the SVZ and patient survival.
Similar to previous work [9
], we found that patients with GBM which contacted the SVZ trended with shorter survival. One possibility is that shortened survival may be related to tumor size, as tumors that contact both the cortex and SVZ tend to be large. However, previous reports have shown little correlation between GBM size and survival [11
]. Additionally, Barami et al. [21
] found that contact with the ventricular wall was independent of size.
Another possibility is that tumors that contact the SVZ have higher rates of multifocal or subependymal/leptomeningeal spread. We did not find a significant difference in rates of non-local recurrence between tumor groups based on SVZ contact. And only one patient had leptomeningeal recurrence. Unlike Lim et al. [9
] we found that group III tumors had the highest rates of multifocal disease, both at initial presentation and at recurrence. Thus it is unclear if tumors that contact the SVZ have more aggressive patterns of recurrence. Small sample sizes may account for these discordant results.
There was a difference in gross total resection rates between groups. Group I tumors (those that contact both the ventricle and cortex) had a lower gross total resection rate than other tumors. Since complete resection is associated with better survival [22
], this could be a potential confound for the survival data. Additionally, deeper tumors may have more impact on critical structures, increasing their impact on disability. Thus we cannot say whether tumors that contact the SVZ are intrinsically more malignant than those that do not.
We found no relationship between stem-cell gene expression and SVZ grade. Specifically there was no correlation in expression between the selected stem cell genes, and there was no enrichment of stem cell genes in tumors that contacted the SVZ. Although not correlated with tumor location, expression of several stem cell genes, including CD133, was associated with shortened survival, similar to previous reports [12
]. For instance, Zhang et al. [23
] found that CD133 expression was negatively correlated with both overall survival and progression-free survival. CD133 expression has been shown to be associated with resistance to radiation and chemotherapy [24
]. Similar results have been demonstrated in mice models of GBM [25
]. Interestingly, BMP4 has been hypothesized to down-regulate CD133 and increase survival in a mouse model [26
]. Although there was no significant correlation between CD133 and BMP4 expression, increased BMP4 expression was associated with longer survival.
Unlike the report of Zhang et al. [23
] we found that higher nestin expression was associated with longer survival. Some differences between the two experiments are notable. Zhang measured protein level with immunohistochemistry, whereas we examined gene expression. Zhang also looked at grade II–IV tumors, whereas we restricted our analysis to grade IV tumors (GBM). Another group [27
] found no difference in survival based on nestin expression levels. Similarly, increased OLIG2 expression was associated with longer survival. OLIG2 is associated with oligodendrogliomal lineage development [17
], and an oligodendroglioma component and genetic signature have previously been shown to be associated with longer survival [28
]. Another gene whose expression was associated with longer survival was MAPK8 (also known as JNK). Previously it has been shown that in cultured glioma cells, inhibition of this kinase reduces VEGF secretion [29
]. Since VEGF is associated with malignancy, this may explain why patients with tumors with lower MAPK8 gene expression had longer survival.
Since patients in group I + II trended with shorter survival, we also analyzed the expression of genes in SVZ-contacting tumors compared to those that did not contact the SVZ in order to look for candidate genes that may be involved with shorter survival. Several genes, including CARM1 and LOXL2, over-expressed in SVZ-contacting tumors, were associated with poor survival. LOXL2 has been shown to promote cell migration in breast cancer [30
], and is associated with a poor prognosis in squamous cell carcinomas [31
], but this is the first report of an association with poor survival in GBM. CARM1 promotes breast cancer proliferation through an estrogen-dependent mechanism [32
], but has no known role in glioma malignancy.
Interestingly, although no stem-cell gene expression signature was associated with SVZ group II, many genes associated with the immune system were over-expressed in group II, including several MHC genes. This is of potential importance as MHC expression modulates response to dendrictic cell therapy currently being developed to treat GBM, and thus tumors that contact the SVZ may respond differently to this treatment compared to other tumors [33
]. Additionally, it has been shown that migrating glioma cells down-regulate MHC class II genes. If the SVZ is the origin for gliomagenic cells, this suggests that high expression of these genes may account for the lack of spread of group II tumor progenitor cells away from the SVZ prior to tumor formation [34
In conclusion, we found no evidence that tumors contacting the SVZ were more likely, based on gene expression, to be “stem-cell-derived”, than tumors not contacting the SVZ. Two possible explanations are: (1) the SVZ is not the origin for tumor producing cells; or (2) cells responsible for gliomagenesis are produced in the SVZ but migrate towards the cortex before tumorigenesis. The second hypothesis is supported by animal studies which have shown that gliomas arising from the periventricular region can grow along white matter tracts, losing their connection to the SVZ [35
]. We did find, however, that SVZ-contacting cells over-expressed several genes associated with patient survival and with the immune system. The expression of immune-related genes could impact response to treatment, and may mediate cell migration away from the SVZ. Thus, more research is required to clarify the relationship between migration of SVZ derived cancer stem cells and the temporal relationship to gliomagenesis.