Publisher Summary This chapter focuses on the degree of involvement of immune mechanisms in modifying tumor formation and growth during chemical carcinogenesis. During the past two decades, the concept that tumors express antigens against which the host is capable of evoking an immune response has been firmly established. The validity of these studies, as well as comparable findings with MC-induced rat sarcomas (Baldwin, 1955), was critically analyzed by Prehn and Main (1957) who conclusively showed that the induction of immunity to transplanted sarcoma grafts was a tumor-specific phenomenon because immunized mice could still accept skin grafts from the tumor donor, precluding the involvement of an alloantigenic immune response. Evidence shows that tumor rejection antigens are specific and permanent, or quasi-permanent, characteristics of cells transformed by chemical carcinogens. Chemically induced tumors also express antigens normally present in embryonic, but not adult, tissue that may be viewed as the products of dedifferentiation processes induced by the carcinogen, and concurrently there is frequently a deletion of normal tissue antigens. The immunological responses to neoantigens expressed on preneoplastic and neoplastic cells can influence, either positively or negatively, the course of chemical carcinogenesis.

Immunological aspects of chemical carcinogenesis.

Publisher Summary Several lines of evidence suggest that glycosphingolipids (GSLs) are involved in growth control. In accordance with this hypothesis, cell transformation always results in a variety of alterations in different classes of GSL. Only certain of these transformation-associated GSL changes correlate with tumor genesis and metastasis. GSL changes associated with malignancy do not stop at the first stage of a transforming event, but continue on as a cascade of changes with progression of the malignancy. Changes in GSL composition of transformed cells seem to occur not only at the surface membrane, but also at other inner membranes where GSLs are localized. The altered GSL composition seen in transformed cell membrane is due to a repression of glycosyltransferases and probably is mediated by an increase in catabolism as well. These transformation-associated changes in membrane GSL often result in an antigenic change and several tumor-associated GSL antigens are described in various tumor tissues. It also introduces malignant transformation, which also results in various glycoproteins (GP) changes. Malignant transformation also results in various GP changes. These include a loss of fibronectin that binds to collagen, proteoglycans, and gangliosides and acts as an intercellular matrix GP. Therefore, the loss of fibronectin might result in a release of tumor cells from the site of origin.

Cell surface glycolipids and glycoproteins in malignant transformation.

Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their structural analysis, occurrence, and functions is fascinating and described in this review. Reports from different researchers on apparently similar substances from a variety of biological materials led to the identification of a 9-carbon monosaccharide, which in 1957 was designated "sialic acid." The most frequently occurring member of the sialic acid family is N-acetylneuraminic acid, followed by N-glycolylneuraminic acid and O-acetylated derivatives, and up to now over about 80 neuraminic acid derivatives have been described. They appeared first in the animal kingdom, ranging from echinoderms up to higher animals, in many microorganisms, and are also expressed in insects, but are absent in higher plants. Sialic acids are masks and ligands and play as such dual roles in biology. Their involvement in immunology and tumor biology, as well as in hereditary diseases, cannot be underestimated. N-Glycolylneuraminic acid is very special, as this sugar cannot be expressed by humans, but is a xenoantigen with pathogenetic potential. Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses. Sialyltransferases, which are responsible for the sialylation of glycans and elongation of polysialic acids, are studied because of their significance in development and, for instance, in cancer. As more information about the functions in health and disease is acquired, the use of sialic acids in the treatment of diseases is also envisaged.

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Exploration of the Sialic Acid World.

Hirst (1945; 1948) was the first to suggest that the substrate for the “receptor destroying enzyme” of influenza virus, later recognized as sialidase (neuraminidase, see Chapter 10), was a carbohydrate compound located in the outer membrane of the red blood cell after observing that periodate oxidation “destroys” the cellular receptor. This suggestion was supported by Fazekas de St. Groth (1949), who was able to eliminate by mild periodate oxidation the substrate activity without impairing the adsorption of the influenza virus. In the following years, the cellular receptors for the influenza virus were shown to contain galactose, galactosamine, and sialic acid (McCrea, 1954; Klenk and Stoffel, 1956; Yamakawa et al., 1956) and, in 1957, Klenk and Lempfrid isolated pure, crystalline N-acetylneuraminic acid after neuraminidase treatment of human erythrocytes. Since erythrocyte stroma contains sialic acid residues linked to gangliosides or glycoproteins, it may be assumed that sialic acid exists as a component of these two classes of compounds at the surface of the cell.

The Biological Role of Sialic Acid at the Surface of the Cell

Chemical structure of epiglycanin, the major glycoprotein of the TA3-Ha ascites cell. The carbohydrate chains.

The effect of neuraminidase on the immunogenicity of the Landschutz ascites tumour: site and mode of action

K D Bagshawe

Papers

The effect of neuraminidase on the immunogenicity of the Landschütz ascites tumour: site and mode of action.