Galectin-1-Expression und Inhibition in humanen Glioblastomen
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Beschreibung
Despite intense research effort the prognosis for human glioblastoma is always fatal and there is a lack of molecular understanding and tumor specific treatment strategies. Galectin-1 is a protein, that is overexpressed in many malignancies and involved in tumorproliferation, -progression and therapy resistance. In gliomas Galectin-1 overexpression is associated with worse prognosis. The aim of the current study was to investigate Galectin-1-expression in human glioblastoma, IDH-wildtype, compared to normal brain tissue and cultured human astrocytes as well as the impact of Galectin-1-expression on patient survival. In a second step the effect of the allosteric Galectin-1-inhibitor OTX008 on glioblastoma cell viability and their Galectin-1-expression was evaluated.
In 31 patient derived glioblastoma cell cultures, 4 normal brain tissue specimen and cultured human astrocytes Galectin-1 mRNA expression was quantified by q-PCR. From 28 of those patients tissue was available for immunohistochemical staining and quantification of Galectin-1. Expression above the median was defined as high Galectin-1 expression (HGE) and below the median as low Galectin-1 expression (LGE). Groups were compared. Impact on patient survival was investigated by Kaplan-Meier-Method.
OTX008 was administered in various doses in the immortalized glioblastoma models A172 and U87, in 10 of the 31 patient derived cell cultures and in a culture of human astrocytes. After 72h cell viability was measured by MTT-assay. Dose-response-curves were calculated by probit analysis. Afterwards glioblastoma cells were treated with IC50 of OTX008 and Galectin-1-expression was evaluated by q-PCR and compared with untreated controls.
Galectin-1 was found to be overexpressed in glioblastoma compared to normal brain tissue. There was no correlation with MGMT-promotor methylation status. High Galectin-1-expression in glioblastoma is associated with a shorter progression free survival.
OTX008 inhibited cell viability of all glioblastoma cell cultures but had no impact on human astrocytes. Dose-response-relation was dependent on Galectin-1 expression level but not on MGMT-promotor methylation status. Galectin-1-expression was not influenced by OTX008.
These results go hand in hand with what is suggested by earlier publications. High Galectin-1-expression might be a negative prognostic factor for human glioblastoma, but this association needs to be evaluated and validated in a larger patient collective. However, OTX008 showed promising inhibition of glioblastoma cell survival. Further investigations, especially regarding the mechanisms of action of OTX008 and possible combination treatments could lead to encouraging new treatment strategies for human glioblastoma.
Autor*in
Hanna Gött
Themen in »Galectin-1-Expression und Inhibition in humanen Glioblastomen«
Medizinische Forschung Glioblastoma Galectin-1-Expression