Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Abstract

Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis.

Proteomic Portrait of Human Breast Cancer Progression Identifies Novel Prognostic Markers

“…CRABP2 binds all-trans retinoic acid in the cytoplasm and targets it to the nucleus where it binds its receptor and promotes cell differentiation. In head and neck cancers and gliomas, CRABP2 levels were shown to be reduced (48,49). In contrast to these tumor types and in support of our data, ErbB2 has been shown to induce retinoic acid resistance in breast cancer cells (50).…”

Retinoic acid signaling and neuronal differentiation

“…One possible hypothesis for resistance is that RA can be channeled to a pro-proliferative, oncogenic pathway depending on the relative abundance of the RAtransporting proteins CRABP2 and FABP5 (reviewed in [252]). In high-grade, undifferentiated, metastasized glioma, CRABP2 is down-regulated and FABP5 is upregulated [253,254], which may divert RA towards the PPARb/d pathway (promoting cell survival) and away from RARs (which promote differentiation) [255,256]. This hypothesis is intriguing, but much more research is needed to test it.…”

FABP5 (fatty acid binding protein 5 (psoriasis-associated))

“…In keeping with other types of cancers, a high ratio of FABP5 to CRABP2 in pancreatic ductal adenocarcinoma cell lines correlates with poor response to RA, whereas CRABP2 expression in the absence of FABP5 correlates with growth inhibition in the presence of RA (Gupta et al, 2012). A number of RA signaling proteins, including FABP5, are highly expressed in high-grade astrocytomas, with FABP5 expression correlating with an undifferentiated tumor phenotype (Campos et al, 2011). The ratio of FABP5 to CRABP2 was found to correlate with survival time in grade IV astrocytoma patients, with a high FABP5 to CRABP2 ratio associated with shorter term survival (Barbus et al, 2011).…”