Induction of meningioma stem signature via hydrogel reprogramming and application of meningioma stem cell marker CXCR4 to pathological diagnosis and treatment

Backgrounds:

Meningioma accounts for about 40% of brain tumors, but there was no effective treatment for recurrent or inoperable cases. We have previously found that when cancer cells are cultured on certain hydrogels, cancer stem cells are efficiently induced in various cancer types and we named this process as hydrogel activated reprogramming (HARP) phenomenon. In this study, we aimed to identify a key molecule that induced meningioma stem cells via hydrogels.

Methods

Meningioma cells cultured on hydrogels were analyzed for expression of regular stem cell markers and their tumor genericity. Microarray analysis was performed to identify meningioma stem cell specific markers and to examine the application of such marker molecules as a therapeutic targets or pathological diagnosis for grading.

Results

Regular stem cell markers such as Nanog , and Oct3/4 were induced by culturing meningioma cells on hydrogels, and comprehensive gene expression analysis identified molecules involved in cancer stem cell activity. Among them, CXCR4 was selected as a therapeutic target molecule. Stimulation of CXCR4 via CXCL12 led to an increase in stem cell markers. In human meningioma pathological specimens and cultured cell lines, there was a correlation between CXCR4 expression levels and NF2 mutations and/or deletions. CXCR4 immunohistochemistry also detected along with the brain invasion. Thus, CXCR4 immunohistochemistry may be useful to suggest typical CNS WHO grade 1 meningioma, that do not require molecular analysis.

Conclusions

We have defined meningioma stem cell signature via HARP phenomenon and identified CXCR4 with biological significance as being diagnostic target.

Key Points

• We induce meningioma stem signature via Hydrogel activated reprogramming (HARP) phenomena.

• We identified CXCR4 as a candidate molecule as stemness marker and therapeutic target.

• Translational research using pathological specimens reveal CXCR4 immunohistochemistry has been shown to play an auxiliary role in the diagnosis of meningiomas.

Importance of the Study

In addition to morphology, immunohistochemistry and gene alteration are being adopted as diagnostic criteria for CNS tumors. From CNS5 onwards, epigenetic changes such as methylation analysis are being adopted as diagnostic criteria. We induced epigenetic changes in meningioma cells and induced cancer stemness, and this technique will be of great importance in the research and diagnosis of meningioma. In addition, microarray analysis was used to select CXCR4 from the molecules that increased simultaneously during stem cell induction on the three hydrogels, and further analysis revealed that CXCR4 immunostaining may indicate the distribution of meningioma stem cells, also making it useful for diagnosis. This report will contribute to the advancement of meningioma research and diagnosis by conducting basic research and using histopathological specimens.