heparitin-sulfate and Wilms-Tumor

While it has been long appreciated that sugar-modified proteins coat the cell surface, their functions are poorly understood. Here, I describe recent genetic studies that demonstrate that one class of sugar-modified proteins, cell-surface proteoglycans, play crucial roles in morphogenesis, growth regulation and tumor suppression. Mutations that affect individual proteoglycans or the enzymes required for glycosaminoglycan synthesis regulate Wingless and Decapentaplegic signaling in Drosophila, and body size in mice and humans. Compromising proteoglycan function is also associated with the development of Wilm's tumors and hereditary multiple exostoses. In this review, these biological findings are placed in the context of proteoglycan biochemistry and molecular function.

Topics: Animals; Body Patterning; Drosophila Proteins; Glycosaminoglycans; Growth Substances; Heparitin Sulfate; Humans; Insect Proteins; Membrane Glycoproteins; Mice; Proteoglycans; Proto-Oncogene Proteins; Signal Transduction; Wilms Tumor; Wnt1 Protein

Deletions in the heparan sulphate proteoglycan encoding glypican 3 (GPC3) gene have recently been documented in several Simpson-Golabi-Behmel syndrome (SGBS) families. However, no precisely defined SGBS mutation has been published. We report here a 13 base pair deletion which causes a frameshift and premature termination of the GPC3 gene in the Dutch-Canadian SGBS family in whom the trait was originally mapped. Our analysis shows that a discrete GPC3 disabling mutation is sufficient to cause SGBS. Furthermore, our finding of a GPC3 normal daughter of an SGBS carrier with skeletal abnormalities and Wilms tumour raises the possibility of a trans effect from the maternal carrier in SGBS kindreds.

Topics: Bone and Bones; Canada; Chromosomes, Human, Pair 11; Female; Frameshift Mutation; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Male; Pedigree; Proteoglycans; Sequence Analysis, DNA; Sequence Deletion; Syndrome; Wilms Tumor; X Chromosome

The glycosaminoglycans of the tumor mass and from the urine of patients with a nephroblastoma of embryonic origin (Wilms' tumor) and hypernephroma were analyzed. The urine of patients with Wilms' tumors prior to treatment, and two patients with metastasis contained high levels of hyaluronic acid (2-5 mg/l of urine) when compared to patients after surgery or chemotherapy where the content of hyaluronic acid was less than 0.1 mg/l. Urine of patients with hypernephroma and normal individuals contained even smaller amounts of hyaluronic acid. Normal kidneys contain mainly dermatan sulfate and heparan sulfate, while the hypernephroma and Wilms' tumor contain substantial amounts of chondroitin sulfate. The amount of glycosaminoglycans isolated from Wilms' tumor and hypernephroma were 10 times and 3 times, respectively, greater than normal kidneys. The amounts of hyaluronic acid in Wilms' tumor varied from 56 to 73% whereas normal kidneys contained about 13%. Chondroitin sulfate was also increased in Wilms' tumor and hypernephroma. It corresponded to 11% and 42%, respectively, of the total glycosaminoglycans. These and other findings indicate that the glycosaminoglycans of Wilms' tumors resemble those present during embryonic development of normal tissues whereas those in hypernephroma are typical of other carcinomas of different origins.

Topics: Carcinoma, Renal Cell; Dermatan Sulfate; Disaccharides; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Kidney Neoplasms; Wilms Tumor