Ceramide levels are inversely associated with malignant progression of human glial tumors.
Ceramide represents an important sphingoid mediator involved in the signaling pathways that control cell proliferation, differentiation, and death. To determine whether ceramide levels correlate with the malignant progression of human astrocytomas, we investigated these levels in surgical specimens of glial tumors of low-grade and high-grade malignancy. Tumor samples obtained from 52 patients who underwent therapeutic removal of primary brain tumors were used. The tumors were classified according to standard morphologic criteria and were grouped into tumors of low-grade and high-grade malignancy. Sections of normal brain tissue adjacent to the tumor were also analyzed in 11 of the 52 patients. After extraction and partial purification, ceramide was measured by quantitative derivatization to ceramide-1-phosphate using diacylglycerol kinase and [gamma-(32)P]ATP. Ceramide levels were significantly lower in the combined high-grade tumors compared with low-grade tumors and in both tumor groups compared with peritumoral tissue. The results indicate an inverse correlation between the amount of ceramide and tumor malignancy as assessed by both the histological grading and ganglioside pattern. Moreover, overall survival analysis of 38 patients indicates that ceramide levels are significantly associated with patient survival. The present findings indicate that ceramide is inversely associated with malignant progression of human astrocytomas and poor prognosis. The downregulation of ceramide levels in human astrocytomas emerges as a novel alteration that may contribute to glial neoplastic transformation. The low ceramide levels in high-grade tumors may provide an advantage for their rapid growth and apoptotic resistant features. This study appears to support the rationale for the potential benefits of a ceramide-based chemotherapy.
Department of Medical Chemistry and Biochemistry, Study Center for the Functional Biochemistry of Brain Lipids, University of Milan, LITA-Segrate, Segrate, Milan, Italy. laura.riboni@unimi.it
Laura
L
Riboni
Rolando
R
Campanella
Rosaria
R
Bassi
Roberto
R
Villani
Sergio M
SM
Gaini
Filippo
F
Martinelli-Boneschi
Paola
P
Viani
Guido
G
Tettamanti
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001254:Astrocytoma / Q000145:classification / Q000378:metabolism*; D001932:Brain Neoplasms / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate
D002518:Ceramides; D005732:Gangliosides; D009419:Nerve Tissue Proteins; C026226:ganglioside, GD3; D004247:DNA