gms | German Medical Science

Objective: In gliomas, undifferentiated tumor cells influence tumor growth and seem to be irresponsive to physiological differentiation stimuli, persisting in an undifferentiated developmental state associated with high tumorigenicity and therapy resistance. Here we investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity and impact on patient prognosis.

Methods: Expression of key-molecules belonging to the RA differentiation pathway was analyzed on a tissue microarray, consisting of tumor samples from 283 astrocytic gliomas WHO II-IV. Protein expression was correlated with tumor grade, tumor differentiation and patient survival data.

Results: In sharp contrast to other tumor entities, gliomas featured a malignancy-dependent increase in the expression of molecules belonging to the RA synthesis machinery. In detail, this included tumor grade-dependent expression of 1) the intracellular RA-binding protein CRBP1 (p<0.001) catalyzing cellular retinoid uptake, 2) ALDH1A1 (p=0.012) capable of activating RA precursors and 3) the RA-degrading enzyme CYP26B1 (p<0.001). On the other hand, expression of the natural RA-binding protein CRABP2 which fosters differentiation decreased with tumor malignancy (p<0.001). This was further aggravated by increased expression of the intracellular RA-binding protein FABP5 (p<0.001), which can hinder RA-induced differentiation diverting RA into a tumor-promoting pathway. Supporting this assumption, high expression of CRBP1 was associated with increased tumor cell proliferation (p<0.001) and elevated FABP5 levels correlated with an undifferentiated and more aggressive tumor phenotype (p=0.003). Finally, ALDH1A1, discussed as potential (cancer) stem-cell marker besides its involvement in RA signalling, proved to be an independent marker for poor patient survival (p=0.016).

Conclusions: Our data indicate that a complex deregulation in the RA pathway exerts an unfavourable influence on patient prognosis and seems to be involved in the loss of the differentiation capacity in gliomas.