Sialylation and malignant potential in tumour cell glycosylation mutants

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Abstract
Somatic mutations and drugs that either reduce η1-6GlcNAc-branching of N-linked oligosaccharides or block the addition of terminal sequences containing galactose and sialic acid have been shown to inhibit tumour growth and metastasis. In an attempt to further define the oligo-saccharide sequences that contribute to the malignant phenotype, we have selected spontaneous wheat germ agglutinin-resistant (WGAR) mutants from highly meta-static murine lymphoid tumour cells and characterized four mutant phenotypes. Mutants were selected from VM4, a clone of the MDAY-D2 tumour cell line which had been transfected with the bacterial η-galactosidase gene (LacZ). VM4 cells retained the malignant phenotype of MDAY-D2 and the cells expressed LacZ, which facilitated the counting of metastases as the tumour cells stained blue when incubated with 5-bromo-4-chloro-3-indolyl η-D-galactopyranoside (X-gal). The most frequently isolated mutant was defective in the transport of UDP-Gal into the Golgi, and as previously observed for this mutation, the cells were non-metastatic and produced very slow-growing solid tumours. Mutants expressing CMP-SA hydroxylase, and consequently glycoconjugates with N-glycolylneuraminic acid (NeuNGc), remained highly metastatic, but grew more slowly than VM4 cells as s.c. tumours in mice. A novel WGAR mutant showing a large increase in Galηl-4GlcNAc:a2-6 sialyltransferase (SA-T) mRNA levels (ST6N) and enzyme activity was observed to be less metastatic and also grew more slowly at the s.c site of inoculation. Finally, a fourth phenotypic class of WGAR mutants showed a complex phenotype including expression of a ηGal-binding cell surface lectin and reduced sialylation of glycoconjugates. These results suggest that changes in either the amount, the type or linkage of sialic acid in tumour cell glycoconjugates can affect tumour growth and metastasis.

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