gms | German Medical Science

Objective: Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) have emerged as treatment modalities for vestibular schwannomas. However at the same time cases that require surgical salvage after failed radiation are increasing. In other tumor entities microenvironmental changes regarding interactions between tumor cells and non-tumor cells (e.g. fibroblasts, vascular endothelial cells, components of the immune system), also defined as the tumor stroma, are known to contribute to radioresistance by uncontrolled extracellular matrix remodeling. The aim of this study was to investigate microenvironmental and molecular changes in particular the role of extracellular matrix components and components of the immune system in vestibular schwannomas after failed radiosurgery.

Method: 36 non-irradiated and 7 irradiated vestibular schwannomas were fresh-frozen at the time of surgical resection and RNA isolation was performed for cDNA microarray analysis (HG-U219 Array Plate, Affymetrix^®). Identified differentially expressed genes were analyzed by gene ontology regarding known regulators and mediators of fibrosis, extracellular matrix and immune cell components. Standard neuropathological examination was performed in all cases.

Results: The previously irradiated tumours showed marked regressive changes. Comparing the two groups we detected a total of 99 differentially expressed genes (90 genes were up- and 9 downregulated) with significant difference in up- and downregulation based on the criteria of P value < 0.01 and absolute fold change ≥ 2. Remarkably, among the top upregulated genes 9 genes were involved in mediation of fibrosis and extracellular matrix organization and 12 genes represent components of the immune system.

Conclusions: Neuropathologic and genetic results suggest that there is an uncontrolled extracellular matrix remodeling which promotes a connective tissue remodeling and regressive histopathologic changes (e.g. scarring, fibrosis, necrosis) in irradiated vestibular schwannomas. On the one hand this might be the reason why surgery is more demanding and the clinical outcome is worsened in these cases; on the other hand changes in microenvironment in particular uncontrolled remodelling of extracellular matrix through overexpression of extracellular matrix components possibly contributes to radioresistance and progressive growth of vestibular schwannoma tumor cells.