i(3)so3-galactosylceramide and Ovarian-Neoplasms

Among negatively charged lipids, sulfoglycolipids are known to be expressed by specific cell populations and to be involved in their functions, including in adhesion with functional proteins, modification of ion channels and induction of cellular differentiation. Accordingly, we determined their amounts in several histologically defined types of ovarian carcinoma tissues. Sulfoglycolipids were determined by TLC-immunostaining with monoclonal anti-sulfatide antibodies and the gene expression of their synthetic enzymes was by RT-PCR. All types of ovarian carcinomas were revealed to exhibit potential to synthesize sulfoglycolipids, either sulfatide (I(3)SO3-GalCer) or sulfated lactosylceramides (II(3)SO3-LacCer), which were expressed at the following frequencies, 6 out of 6 mucinous cystadenocarcinomas, 4 out of 7 serous cystadenocarcinomas, 2 out of 3 endometrioid carcinomas, and 2 out of 3 clear cell adenocarcinomas. All mucinous cystadenocarcinoma tissues preferentially contained sulfatide in amounts of 0.61-1.13 μg per mg dry weight, the molecular species being similar with those of GalCer. Whereas the other carcinomas contained either sulfatide or sulfated LacCer, the latter being detected in 4 out of 6 specimens with sulfoglycolipids. The expression of sulfatide and sulfated LacCer was found to be positively correlated with the amounts of GalCer and LacCer as substrates for sulfotransferase and expression of the genes for GalCer sulfotransferase and ceramide galactosyltransferase. Sulfoglycolipids in ovarian carcinoma tissues were revealed to be expressed in morphologically defined type-characteristic manners, in contrast to the ubiquitous distribution of GM3.

Topics: Adenocarcinoma, Clear Cell; Carcinoma, Endometrioid; Cystadenocarcinoma, Mucinous; Cystadenocarcinoma, Serous; Female; Glycolipids; Humans; Lactosylceramides; N-Acylsphingosine Galactosyltransferase; Ovarian Neoplasms; Sulfoglycosphingolipids; Sulfotransferases; Sulfuric Acid Esters

Sulfatides (ST) are a category of sulfated galactosylceramides (GalCer) that are elevated in many types of cancer including, possibly, ovarian cancer. Previous evidence for elevation of ST in ovarian cancer was based on a colorimetric reagent that does not provide structural details and can also react with other lipids. Therefore, this study utilized mass spectrometry for a structure-specific and quantitative analysis of the types, amounts, and tissue localization of ST in ovarian cancer, and combined these findings with analysis of mRNAs for the relevant enzymes of ST metabolism to explore possible mechanisms.. Analysis of 12 ovarian tissues graded as histologically normal or having epithelial ovarian tumors by liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI-MS/MS) established that most tumor-bearing tissues have higher amounts of ST. Because ovarian cancer tissues are comprised of many different cell types, histological tissue slices were analyzed by matrix-assisted laser desorption ionization-tissue-imaging MS (MALDI-TIMS). The regions where ST were detected by MALDI-TIMS overlapped with the ovarian epithelial carcinoma as identified by H & E staining and histological scoring. Furthermore, the structures for the most prevalent species observed via MALDI-TIMS (d18:1/C16:0-, d18:1/C24:1- and d18:1/C24:0-ST) were confirmed by MALDI-TIMS/MS, whereas, a neighboring ion(m/z 885.6) that was not tumor specific was identified as a phosphatidylinositol. Microarray analysis of mRNAs collected using laser capture microdissection revealed that expression of GalCer synthase and Gal3ST1 (3'-phosphoadenosine-5'-phosphosulfate:GalCer sulfotransferase) were approximately 11- and 3.5-fold higher, respectively, in the ovarian epithelial carcinoma cells versus normal ovarian stromal tissue, and they were 5- and 2.3-fold higher in comparison with normal surface ovarian epithelial cells, which is a likely explanation for the higher ST.. This study combined transcriptomic and lipidomic approaches to establish that sulfatides are elevated in ovarian cancer and should be evaluated further as factors that might be important in ovarian cancer biology and, possibly, as biomarkers.

Topics: Female; Gene Expression Profiling; Humans; Lipids; Mass Spectrometry; Ovarian Neoplasms; Sulfoglycosphingolipids

Sulfatide-containing liposomes composed of PC, cholesterol, and sulfatide in a molar ratio of 7:2:1 entrapped ADM most efficiently among the negatively-charged liposomes tested. A unilamellar vesicle entrapped 123 ADM molecules, of which 6 molecules are localized in the internal space of the vesicle, 4 molecules are embedded into the membrane matrix, and 113 molecules are bound to the inner surface of the liposomal membrane. Highly efficient entrapment of ADM by the liposomes seems to be due to their rigidity. By the experiment using ovarian tumor-bearing nude mice, it was found that the liposome-entrapped ADM was maintained at much higher blood level, at lower concentration in the heart, and at higher concentration in the tumor than the free drug. The antitumor activity of the liposome-entrapped ADM was comparable with that of the free drug. The body weight of the animals was not affected by the former, whereas it was drastically decreased by the latter.

Topics: Adenocarcinoma; Animals; Doxorubicin; Drug Carriers; Endometriosis; Female; Liposomes; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Sulfoglycosphingolipids

Sulfatide-containing liposomes showed the highest degree of adriamycin entrapment of all the liposomes tested. Adriamycin was bound to the sulfatide anions on the liposomal membrane, inserted into the membrane, and incorporated into the aqueous compartment of the vesicle. Liposome-entrapped adriamycin was maintained at a much higher blood level than free adriamycin, and reached a lower concentration in the heart than did the free drug, which might lead to lower cardiotoxicity of the drug. Incorporation of adriamycin into ovarian tumor transplanted into nude mice was increased when entrapped by the sulfatide-containing liposomes. Liposome-entrapped adriamycin did not induce the drastic loss of body weight which occurred with the free drug. The growth of ovarian tumor was inhibited by liposome-entrapped adriamycin to the same degree as free adriamycin. Having these advantages, sulfatide-containing liposomes could be useful carriers of adriamycin for cancer chemotherapy.

Topics: Animals; Doxorubicin; Female; Liposomes; Mice; Mice, Nude; Ovarian Neoplasms; Pharmaceutical Vehicles; Sulfoglycosphingolipids; Tissue Distribution