Tumor cell surface carbohydrate and the metastatic phenotype

Abstract

The synthesis and expression of cell surface carbohydrates is a developmentally regulated process that appears to affect a number of cell-cell interactions. To determine whether specific oligosaccharide structures present on highly malignant cells are required for expression of the metastatic phenotype, we have isolated lectin resistant tumor cell mutants with defects in the biosynthesis of oligosaccharides. The mutants selected from the highly aggressive lymphoreticular-like tumor line MDAY-D2 were grouped into genetic complementation classes, compared for metastatic ability and for changes in cell surface glycoconjugates. The Asn-linked oligosaccharides and glycolipids of class 1 mutants were deficient in both sialic acid and galactose and the cells showed a greatly attenuated metastatic phenotype compared to the parental cells. A revertant of the class 1 mutation selected in vitro regained the wild type glycoconjugate profile and the highly metastatic phenotype indicating a direct association between the mutation and the loss of metastatic potential. Class 2 mutants remained highly metastatic and had Asn-linked oligosaccharide structures very similar to those found in the wild type cells with N-glycolylneuraminic acid rather than the N-acetylneuraminic acid. Swainsonine, an inhibitor of golgi alpha-mannosidase II, blocks the synthesis of complex-type Asn-linked oligosaccharides resulting in the expression of hybrid-type oligosaccharides at the cell surface and the cells display a lectin resistant phenotype. Although swainsonine inhibited neither tumor cell growth in vitro nor solid tumor growth in situ, the drug dramatically reduced the incidence of lung colonies after i.v. inoculation of both MDAY-D2 and B16F10 melanoma cells. These results, taken together, indicate that certain sialylated Asn-linked oligosaccharides found on metastatic tumor cells are required for expression of the metastatic phenotype.

Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis

“…In an apparently unrelated area of research, many reports showed that carcinoma progression is associated with alterations of cell-surface glycosylation (30)(31)(32)(33)(34). Of note, carcinomas expressing highly sialylated or branched sugar chains and͞or large amounts of mucins have a poor prognosis, because of a high rate of metastasis.…”

“…Of note, carcinomas expressing highly sialylated or branched sugar chains and͞or large amounts of mucins have a poor prognosis, because of a high rate of metastasis. In particular, the expression of sialylated fucosylated glycans like sialyl Lewis x and sialyl Lewis a correlates with a poor prognosis because of tumor progression and metastatic spread (30,31,(33)(34)(35)(36)(37). It was subsequently noted that carcinoma cell-surface mucins carrying sialyl Lewis x/a can be ligands for all three members of the selectin family of cell adhesion molecules (38,39).…”

Quantitative microscopy of mouse colon 26 cells growing in different metastatic sites

“…As with the mirror image exogenous plant lectins more commonly used to probe for metastasis-associated parameters of cancer cell populations, it is not possible at present to ascribe specific functions to their receptors. Nevertheless, lectin-carbohydrate interactions in general have provided a useful index of alterations in glycoconjugates which may be associated with the tumourigenic and metastatic behaviour of cancer cells (Kellokompu, 1986;Raz & Lotan, 1987;Dennis & Laferte, 1987;Lang et al, 1988;Nicolson, 1988;Vavasseur et al, 1990;. The results of the present investigation support the inferences previously drawn from human autopsy data on cases with a history of colorectal carcinoma, and transplantation experiments with colon 26 tumours in mice, both of which indicated that site-associated changes in metastasis-related behaviour can occur in cancer cell populations during their growth in different organs, after their delivery to these anatomic sites.…”

Blocking of N-acetylglucosaminyltransferase V induces cellular endoplasmic reticulum stress in human hepatocarcinoma 7721 cells

“…GnT-V overexpression and its up-regulation during the process of cancerous transformation were observed in many cancers, such as human mammary, colon and hepatic tumor [3][4][5][6][7][8][9]. For liver, in normal hepatic tissue, the GnT-V activity is low, but increases in human hepatocellular carcinoma (HCC) tissues, which is correlated with its progression, and the enzyme activity in human HCC tissues increases during metastasis in vivo [48,49].…”

“…It is not an ubiquitous enzyme, of which expression is regulated in a tissue-specific manner, that distributes mainly in intestine, brain and lung [1,2]. GnT-V as well as its product β-1,6-GlcNAc branch were reported to overexpress in many cancers such as human mammary, colon and hepatic tumor, and it was essential for tumor metastasis as well as for tumor [3][4][5][6][7][8][9]. However it was unchanged in some human renal carcinomas [10], so the role of GnT-V for the transformation of animal cells also may be the tissue-specific.…”