cdw17-antigen and Kidney-Neoplasms

In a xenograft model wherein, live renal cancer cells were implanted under the kidney capsule in mice, revealed a 30-fold increase in tumor volume over a period of 26 days and this was accompanied with a 32-fold increase in the level of lactosylceramide (LacCer). Mice fed D- threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase (LCS: β-1,4-GalT-V), showed marked reduction in tumor volume. This was accompanied by a decrease in the mass of lactosylceramide and an increase in glucosylceramide (GlcCer) level. Mechanistic studies revealed that D-PDMP inhibited cell proliferation and angiogenesis by inhibiting p44MAPK, p-AKT-1 pathway and mammalian target for rapamycin (mTOR). By linking glycosphingolipid synthesis with tumor growth, renal cancer progression and regression can be evaluated. Thus inhibiting glycosphingolipid synthesis can be a bonafide target to prevent the progression of other types of cancer.

Topics: Administration, Oral; Animals; Antigens, CD; Blotting, Western; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Galactosyltransferases; Glucosylceramides; Glucosyltransferases; Kidney; Kidney Neoplasms; Lactosylceramides; Mice; Mice, Inbred BALB C; Morpholines; Peptide Fragments; Proto-Oncogene Proteins c-akt; Signal Transduction; Time Factors; Transcription Factors; Treatment Outcome; Tumor Burden; Tumor Suppressor Protein p53

We have measured the binding and degradation of low-density lipoprotein (LDL) and LDL-mediated effects on cholesteryl ester (CE) synthesis in cultured normal and tumor proximal tubular (PT) cells. The effects of LDL on the regulation of glycosphingolipid metabolism in cells was pursued employing radioactive precursors, e.g., [3H]serine, and [3H]glucose and by measuring the activity of UDP-galactose: glucosylceramide: B1-4 galactosyltransferase (GalT-2). In normal PT cells, there was a saturable and displaceable binding and degradation of 125I-LDL and a LDL mediated 14-fold stimulation of cholesteryl ester (CE) synthesis. This was accompanied by a suppression (70-80%) of incorporation of [3H]glucose and [3H]serine into GlcCer, LacCer, GbOse3Cer and GbOse4Cer and suppression (70-80%) of GalT-2 activity. In tumor PT cells, displaceable binding and degradation of 125I-LDL was not observed and LDL failed to stimulate CE synthesis. In such cells, LDL exerted a concentration-dependent stimulation of [3H]glucose and [3H]serine incorporation into GSL. Maximum stimulation (250%) of GalT-2 activity in tumor PT cells occurred with 25 micrograms LDL/ml medium. We conclude that LDL taken up via receptor mediated pathway decreases GaIT-2 activity in normal PT cells. In contrast, LDL not taken up via the LDL receptor pathway in tumor PT cells failed to suppress the incorporation of [3H]glucose and [3H]serine into glycosphingolipids and GalT-2 activity leading to a stimulation of lactosylceramide synthesis.

Topics: Antigens, CD; Cholesterol Esters; Galactosyltransferases; Glucose; Glycosphingolipids; Humans; Iodine Radioisotopes; Kidney Neoplasms; Kidney Tubules, Proximal; Lactosylceramides; Lipoproteins, LDL; Receptors, LDL; Serine; Tritium; Tumor Cells, Cultured; Up-Regulation

Lactosylceramide sulfate and galactosylceramide sulfate were found to increase markedly in human renal cell carcinoma (adenocarcinoma) as compared to uninvolved tissue. Activities of two sulfotransferases toward galactosylceramide and lactosylceramide as substrates were significantly elevated in the carcinoma compared to the uninvolved tissue resulting in enhanced synthesis of the two sulfatides in the carcinoma. The elevation of the two sulfotransferases was parallel in most tumors, suggesting that the same enzyme is responsible for the enhanced synthesis of two sulfatides. No consistent difference in the activity of arylsulfatase A, which desulfates the two sulfatides, was observed between the carcinoma and uninvolved tissue. Both the present and previous results show that the increased synthesis of the sulfatide(s) due to elevated sulfotransferase activity could be a biochemical characteristic common to adenocarcinomas derived from different tissues.

Topics: Adenocarcinoma; Adult; Aged; Antigens, CD; Carcinoma, Renal Cell; Cerebroside-Sulfatase; Female; Galactosylceramides; Glycosphingolipids; Humans; Kidney Neoplasms; Lactosylceramides; Male; Middle Aged; Sulfoglycosphingolipids; Sulfurtransferases

We performed immunohistochemical examination of serial sections of human fetal and adult renal tissue as well as human renal carcinoma tissue, using monoclonal antibodies T5A7, 1B2, FH2, FH4, and FH6. These monoclonal antibodies were directed to lacto series type 2 antigens with sugar-chain structures: lactosylceramide, lactoneotetraosylceramide (paragloboside), Lex (a chemically well-defined fucosyl carbohydrate antigen), difucosyl Lex, and sialosyl-difucosyl Lex, respectively. The staining pattern in fetal renal tissue changed significantly according to the stage of organogenesis. In addition, expression of the antigens, especially paragloboside and sialosyl-difucosyl Lex, was closely related to the prognosis of the patient. These results suggest that the expression of a series of oncofetal antigens in development or differentiation of organs is reflected in the reversion to an immature pattern of antigenic expression in tumor tissue. The pattern of antigen expression in renal tumors offers a good criterion for ascertaining the degree of tumor differentiation and malignancy and is valuable for determining prognosis.

Topics: Adult; Antibodies, Monoclonal; Antigens, CD; Antigens, Neoplasm; Carcinoma, Renal Cell; Embryo, Mammalian; Female; Fetus; Globosides; Glycolipids; Glycosphingolipids; Humans; Immunohistochemistry; Kidney; Kidney Neoplasms; Lactosylceramides; Lewis X Antigen; Neoplasm Staging; Pregnancy; Prognosis