i(3)so3-galactosylceramide and Brain-Neoplasms

Glioblastoma is a prevalent malignant brain tumor and despite clinical intervention, tumor recurrence is frequent and usually fatal. Genomic investigations have provided a greater understanding of molecular heterogeneity in glioblastoma, yet there are still no curative treatments, and the prognosis has remained unchanged. The aggressive nature of glioblastoma is attributed to the heterogeneity in tumor cell subpopulations and aberrant microvascular proliferation. Ganglioside-directed immunotherapy and membrane lipid therapy have shown efficacy in the treatment of glioblastoma. To truly harness these novel therapeutics and develop a regimen that improves clinical outcome, a greater understanding of the altered lipidomic profiles within the glioblastoma tumor microenvironment is urgently needed. In this work, high resolution mass spectrometry imaging was utilized to investigate lipid heterogeneity in human glioblastoma samples. Data presented offers the first insight into the histology-specific accumulation of lipids involved in cell metabolism and signaling. Cardiolipins, phosphatidylinositol, ceramide-1-phosphate, and gangliosides, including the glioblastoma stem cell marker, GD3, were shown to differentially accumulate in tumor and endothelial cell subpopulations. Conversely, a reduction in sphingomyelins and sulfatides were detected in tumor cell regions. Cellular accumulation for each lipid class was dependent upon their fatty acid residue composition, highlighting the importance of understanding lipid structure-function relationships. Discriminating ions were identified and correlated to histopathology and Ki67 proliferation index. These results identified multiple lipids within the glioblastoma microenvironment that warrant further investigation for the development of predictive biomarkers and lipid-based therapeutics.

Topics: Brain Neoplasms; Cardiolipins; Ceramides; Fatty Acids; Gangliosides; Glioblastoma; Humans; Ki-67 Antigen; Mass Spectrometry; Neoplasm Recurrence, Local; Phosphates; Phosphatidylinositols; Sphingomyelins; Sulfoglycosphingolipids; Tumor Microenvironment

We described here a liposomal carrier system in which the targeting ligand was sulfatide, a glycosphingolipid known to bind several extracellular matrix (ECM) glycoproteins whose expression was highly up-regulated in many tumors. In vitro experiments with human glioma cell lines demonstrated that robust intracellular uptake of the liposomes depended specifically on the presence of sulfatide as the key liposomal component. Significant amount of the liposomes remained largely intact in the cytoplasm for hours following their internalization. When anticancer drug doxorubicin (DOX) was encapsulated in such liposomes, most of the drug was preferably delivered into the cell nuclei to exert its cytotoxicity. Use of this drug delivery system to deliver DOX for treatment of tumor-bearing nude mice displayed much improved therapeutic effects over the free drug or the drug carried by polyethylene glycol (PEG)-grafted liposomes. Our results demonstrate a close link between effective intracellular uptake of the drug delivery system and its therapeutic outcome. Moreover, the sulfatide-containing liposomes (SCL) may represent an interesting ligand-targeted drug carrier for a wide spectrum of cancers in which sulfatide-binding ECM glycoproteins are expressed.

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Cell Line, Tumor; Cell Nucleus; Cell Survival; Cytosol; Doxorubicin; Drug Carriers; Drug Delivery Systems; Glioma; Humans; Liposomes; Mice; Mice, Nude; Microscopy, Fluorescence; Neoplasm Transplantation; Sulfoglycosphingolipids; Survival; Transplantation, Heterologous

Primary and metastatic brain tumours may result in an altered exposure of normal cellular components to the immune system inducing an immune response measurable in autoantibodies. One potential immunogenic molecule is sulphatide, the major acidic glycolipid in myelin. Thirty-eight sera from 31 patients with primary and metastatic brain tumours have, therefore, been analyzed for the presence of antisulphatide antibodies by an ELISA performed on thin layer chromatography plates. Twenty-eight of the thirty-eight sera (74%) showed a positive antibody titre to sulphatide. The antibody titres were significantly higher (p < 0.01) in sera from patients with primary brain tumours than in sera from those with metastases. The study lends support to the possibility that antisulphatide antibodies could contribute to tissue damage and this might facilitate the invasive growth in primary brain tumours by demyelination. However, the pathogenic significance of these autoantibodies remains to be further elucidated.

Topics: Adolescent; Adult; Aged; Antibodies, Neoplasm; Brain Neoplasms; Female; Humans; Male; Middle Aged; Myelin Sheath; Sulfoglycosphingolipids

Malignant transformation is characterized by the uncontrolled proliferation of cells. And changes in the composition of glycolipids, cell surface component which may be involved in regulation of cell growth, were often observed in the malignant transformation. In this study, cholesterol, lipid-bound phosphorus, cerebroside, sulfatide and ganglioside were quantitated in the tissue of 20 human malignant brain tumors (malignant glioma, 8; low grade glioma, 4; metastatic tumor, 7; malignant meningioma, 1). As compared with normal brain, all tumor tissue contained lower cholesterol, sialic acid, cerebroside and sulfatide. Metastatic brain tumor or glioma showed characteristic patterns in the content of ganglioside, cerebroside and sulfatide respectively. The ganglioside patterns of metastatic tumor or glioma contained a greater proportion of structurally simpler gangliosides than normal brain. And in metastatic tumor, GM3 was a major ganglioside. On the contrary, glioma had increased proportion of GM3 and GD3 gangliosides. High grade glioma such as Grade 3-4 contained higher proportion of GM3 and GD3, whereas low grade glioma (Grade 1-2) contained less proportion of GM3 and GD3.

Topics: Brain Neoplasms; Cerebrosides; Cholesterol; Gangliosides; Glioblastoma; Glioma; Humans; Lipids; Sulfoglycosphingolipids

In order to utilize liposomes for the treatment of brain tumors, we examined the interaction between the cells and the liposomes prepared from phosphatidylcholine, cholesterol, and sulfatide (molar ratio, 7:2:1), which were able to deliver the encapsulated materials into the brain through the blood-brain barrier. With a variety of human cell lines, the incorporation of the liposomes and the release of the liposomal contents into cells were studied by spectrofluorometry and flow cytometry by use of encapsulated 6-carboxy-fluorescein. It was found that the amounts of liposomes incorporated into cells were dependent on the dose of liposomes and type of cells. At the same concentration of liposomes, the highest incorporation was found for glioma cells, which was further confirmed by electron microscopy with ferritin-containing liposomes. These results indicate that the liposomes composed of sulfatide, phosphatidylcholine and cholesterol have a high affinity for human glioma cells and should be useful for the chemotherapy of glioma when antitumor drugs are encapsulated into them.

Topics: Antineoplastic Agents; Brain Neoplasms; Glioma; Humans; Liposomes; Sulfoglycosphingolipids; Tumor Cells, Cultured

Experimental rat neural tumors in offspring were induced transplacentally by a single injection of a chemical carcinogen, ethylnitrosourea, 20 mg/kg body weight, in the tail vein of the mother. The neutral glycosphingolipid, sulfatide, and ceramide composition of the tumors and the normal tissues from which the tumors originated is described. The content of nonhydroxy fatty acid (NFA) and hydroxy fatty acid (HFA) containing ceramide in all the neural tumors so far examined was significantly increased compared with the corresponding normal neural tissue. Some 8 to 18 mol% of total neutral glycolipids was as ceramide in neurinomas, oligodendrogliomas, and meningiomas. Lactosylceramide in normal neural tissues was about 1 mol% of the total neutral glycosphingolipids. In various neural tumors lactosylceramide increased up to 8 mol%. NFA- and HFA-containing cerebrosides constitute 94-100% of the neutral glycosphingolipids in normal neural tissues. In various neural tumors the mol percent of cerebrosides was significantly reduced. A high performance liquid chromatographic method was modified to analyze simultaneously ceramides, cerebrosides, and higher neutral glycosphingolipids.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Astrocytoma; Brain Neoplasms; Ceramides; Ependymoma; Glioma; Glycosphingolipids; Mass Spectrometry; Neoplasms, Experimental; Peripheral Nervous System Neoplasms; Rats; Sulfoglycosphingolipids

Clonal cell lines derived from both spontaneous and chemically induced rat and mouse brain tumors were screened for their ability to incorporate H232SO4 into galactosyl(3-O-sulfate)ceramide (sulfatide). High levels of 35SO4 incorporation into sulfatide were found only in two of the mouse cell lines studied (G26-20 and -24). Tumors produced by subcutaneous injection of these cell lines into C57BL/6 mice were also unique in that they contained high levels of both sulfatide and galactosylceramide. The synthesis of large amounts of sulfatide and galactosylceramide by a clonal cell line of neurological origin suggests that the original tumor was of oligodendrocyte or Schwann cell origin. In common with a large number of mouse and rat astrocyte cell strains and their derived tumors, these glial cells lacked the ability to synthesize gangliosides such as monosialotetraglycosylceramide and disialotetraglycosylceramide (as judged by analytical and [3H]GlcNH2 incorporation studies). This appears to be a unique characteristic of neuroblastoma-derived cell strains such as N18, NB2a, and NB41A.

Topics: Animals; Brain Neoplasms; Clone Cells; Glioma; Glycosphingolipids; Mice; Myelin Sheath; Neoplasms, Experimental; Sulfoglycosphingolipids