title: 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.
authors.affiliation: Division of Neurological Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.forename: Franz-Simon
authors.initials: FS
authors.lastname: Centner
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Ramadan
authors.initials: R
authors.lastname: Ali
authors.forename: Katharina
authors.initials: K
authors.lastname: Dorsch
authors.forename: Feng
authors.initials: F
authors.lastname: Wan
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Rezvan
authors.initials: R
authors.lastname: Ahmadi
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000080924:Aldehyde Dehydrogenase 1 Family; D001254:Astrocytoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002469:Cell Separation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D050697:Retinal Dehydrogenase; D000072516:Retinoic Acid 4-Hydroxylase; D054840:Retinol-Binding Proteins, Cellular / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D012333:RNA, Messenger; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase