Sialylation and malignant potential in tumour cell glycosylation mutants.
Sialylation and malignant potential in tumour cell glycosylation mutants.
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DOI：
10.1093/glycob/4.5.665
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发表时间：
1994-10
期刊：
影响因子：
4.3
通讯作者：
Ryo Takano;Elaine A. Muchmore;James W-Dennis
中科院分区：
文献类型：
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作者：
Ryo Takano;Elaine A. Muchmore;James W-Dennis
体细胞突变和减少N-连接寡糖的β 1- 6 GlcNAc分支或阻断含有半乳糖和唾液酸的末端序列的添加的药物已被证明可抑制肿瘤生长和转移。在试图进一步定义的寡糖序列，有助于恶性表型，我们已经选择了自发的麦胚凝集素耐药（WGAR）突变体的高转移性小鼠淋巴肿瘤细胞和特征的四个突变体表型。突变体选自VM 4，其是MDAY-D2肿瘤细胞系的克隆，其已用细菌β-半乳糖苷酶基因（LacZ）转染。VM 4细胞保留了MDAY-D2的恶性表型，并且细胞表达LacZ，当与5-溴-4-氯-3-吲哚基β-D-吡喃半乳糖苷（X-gal）孵育时，LacZ促进了转移的计数，因为肿瘤细胞染成蓝色。最常见的分离的突变体是有缺陷的运输UDP-Gal进入高尔基体，和以前观察到的这种突变，细胞是非转移性的，并产生非常缓慢生长的实体瘤。表达CMP-SA羟化酶的突变体，以及因此与N-羟乙酰神经氨酸（NeuNGc）的糖缀合物，保持高度转移性，但在皮下时比VM 4细胞生长更慢。小鼠的肿瘤观察到显示Gal β 1-4GlcNAc：α 2-6唾液酸转移酶（SA-T）mRNA水平（ST 6 N）和酶活性大幅增加的新型WGAR突变体的转移性较低，并且在s.c.接种部位。最后，WGAR突变体的第四表型类别显示出复杂的表型，包括β-半乳糖结合细胞表面凝集素的表达和糖缀合物的唾液酸化减少。这些结果表明，肿瘤细胞糖缀合物中唾液酸的量、类型或键的变化可以影响肿瘤的生长和转移。
Somatic mutations and drugs that either reduce beta 1-6GlcNAc-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 oligosaccharide sequences that contribute to the malignant phenotype, we have selected spontaneous wheat germ agglutinin-resistant (WGAR) mutants from highly metastatic 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 beta-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 beta-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 Gal beta 1-4GlcNAc:alpha 2-6 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 beta Gal-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.