gms | German Medical Science

Objective: Glioblastoma multiforme (GBM) remains a poor curable disease due to its heterogeneity that enables fast and aggressive relapses. This relies on the occurrence of different tumor cell subclones within the tumors including infiltrative “guerilla” cells and tumor initiating/stem cells. Thus, we characterized “guerilla” cells in solid tumors of different malignancy grades according to their gene expression.

Method: We isolated fast migrating glioma cells from 16 solid tumors, graded as astrocytoma, glioblastoma or recurrence, and characterized them by qPCR concerning migration-related genes, stem-like cell markers and individual gene expression profiles related to distinct known GBM subtypes. Furthermore, we tried to imitate recurrent glial tumors in stable cell lines by treatment with a subletal dosis of temozolomide and analyzed these cultures in regard to their migratory and stem-like cell characteristics by qPCR.

Results: Analysis of gene expression profiles of solid gliomas revealed differences not only in “guerilla” cells compared to not-“guerilla” cells, but also with respect to malignancy grades. At this, gene expression of integrins, chemokine receptors, and epithelial-to-mesenchymal transition markers was downregulated in “guerilla” cells of astrocytomas and glioma recurrences, but upregulated in primary glioblastomas indicating a progression-dependent alteration in gene expression. Moreover, specific characteristics of the proneural subtype were exclusively detected in astrocytomas, whereas glioma relapses displayed more neural characteristics. These malignancy-specific observations were mirrored in the expression analysis of stem cell markers as “guerilla” cells of astrocytomas showed low expression of Nestin, CD133, Musashi and Sox2, while the expression was higher in primary glioblastomas. Variations in gene expression could also be identified in vitro in stable GBM cell lines, matching individual characteristics of the four known GBM subtypes, not only regarding the fast and slow migrating cells, but also with respect to temozolomide treated and untreated cells. These differences coincided with the expression of stem cell markers in the respective cell lines.

Conclusions: Our results indicate a distinct expression of migration-related genes in “guerilla” cells in a progression dependent manner within solid tumors. This is in line with individual GBM subtype and stem-like cell characteristics.

Note: Vivian Adamski and Kirsten Hattermann contributed equally.