gms | German Medical Science

Objective: Glioblastomas (GBM) are the most common brain tumors in humans and are effectively incurable. The defining hallmarks of the aggressiveness of GBM are local invasion and neo-angiogenesis. Limited efficacy of patient treatment strategies is due to rapid invasion of surrounding tissue and the fast appearance of chemo- and radioresistant tumor cells often termed cancer stem cells (CSC). Our laboratory has recently shown that Aldehyde Dehydrogenase 1 A1 (ALDH1A1) expressing GBM cells show a CSC phenotype and an increased resistance to Temozolomid (TMZ) compared to ALDH1A1 negative cells.

Method: We investigated a cohort of 35 GBM patients with relapse, which all received combined radio- and chemo-therapy, on the expression of ALDH1A1 in the primary and the recurrent tumor by Immunohistochemistry (IHC) and sensitive single molecule In situ hybridization (ISH). To investigate if ALDH1A1 expressing tumor cells show immunoreactivity for the putative cancer stem cell marker TLX1 we investigated the expression by IHC. As a further top-notch candidate we evaluated the expression of LGR5 in at subset of tumors by sensitive single molecule ISH.

Results: While we observed mostly single ALDH1A1 expressing cells in the primary tumors, the recurrent tumors showed an increase in ALDH1A1 expressing tumor cells. Interestingly, the recently identified CSC marker TLX1 was co-expressed in the ALDH1A1 immunoreactive GBM tumor cells. Here we observed an increased immunoreactivity for TLX1 in recurrent tumors compared to the corresponding primary tumors. Double IHC and IF analysis showed that ALDH1A1 expressing cells were co-immunoreactive for TLX1, rendering this cell population of particular interest for future therapy strategies.

Conclusions: Here we could show that ALDH1A1 is a determinant for GBM patient over all survival and could therefore be used as a diagnostic marker for IHC. So far the molecular regulation of ALDH1A1 expression in GBM cancer cells is still not known. Our data show, that TLX1 is a mediator of a regulatory network for ALDH1A1, as it was reported to regulate ALDH1A1 expression in the hematopoietic system, is a very interesting candidate biomarker for CSC in GBM. Furthermore, the enzyme activity of the ALDH1A1 enzyme detected by MRI might be a possible method to predict patient survival.