[Evolution of the viral-genetic theory of the etiology of malignant tumors].
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Biomedical subjects
Publications and source records attributed to G I Abelev.
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Alpha-fetoprotein (AFP) is an embryo-specific protein of mammalian sera that consists of a single glycosylated polypeptide chain (approximately 70 kD) with 5-6 epitope clusters located on the native molecule. We have elaborated three approaches for the separation of AFP into fractions (variants) that are different in the distinct epitope expression on the native molecule. For this, we have used three technologies largely based on immunoaffinity electrochromatography and electrophoresis/immunoblotting. The separation of these variants was facilitated using monoclonal antibodies previously characterized to the 5 epitope clusters and two individual epitopes on AFP in the ISOBM international workshop. We have shown that these approaches facilitate the identification of cryptic epitopes in AFP, and the relevance of these findings is discussed.
The data considered in the paper indicate that a tumor clone resulting from cell transformation, in order to develop, should overcome a microenvironmental constraint. This destroys intercellular contacts and cell interactions with extracellular matrix required for induction and maintenance of epithelium differentiation. The possible reasons for this lie in mutations of genes that control cell adhesion molecules and integrins, as well as proteases secreted by a tumor. These events lead to partial loss of differentiation antigens by a cell or to their incorrect localization in a cell. Simultaneously, the expression of embryo-specific genes is unblocked, leading to overexpression of embryonic antigens and their abnormal secretion into blood, which results in appearance of oncofetal markers in blood. Discussed from this point of view are alpha-fetoprotein, the carcinoembryonic antigen, and the prostate-specific antigen, which are used as tumor markers.
The role of mechanisms underlying differentiation is considered in malignant transformation of hemoblastoses and epithelial tumors. In hemoblastoses, differentiation is intimately related to malignant transformation and they are underlain by the same mechanisms. Immunophenotyping of hemoblastoses is fully based on successive stages of their differentiation with characteristic expression of differentiation antigens. Unlike hemoblastoses, epithelial tumors gradually, in the course of progression, lose their differentiation due to the degradation of the connections with the microenvironment, which controls the direction and level of epithelial differentiation. Therefore, carcinomas are characterized by varying degrees of "antigenic simplification", including the epithelial-mesenchymal transition.
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alpha-Fetoprotein (AFP) is an embryonic serum protein. Only traces of AFP are present in blood of adult man or animal, but its level substantially increases during liver regeneration and in cases of primary liver carcinoma or embryonic carcinomas. Different aspects of AFP studies (localization of its synthesis, structure and functions, genetic control of its synthesis and its use for cancer diagnostics) are reviewed. The main consideration is given to the cellular mechanisms of regulation of AFP synthesis. Hypothesis of "structural repression of AFP" is substantiated. According to it formation of liver trabeculae leads to suppression of AFP synthesis in hepatocytes, whereas escape of hepatocyte from trabecula results in activation of AFP synthesis. A new experimental model is described: AFP synthesis is activated in primary hepatocyte culture and is suppressed during three-dimensional growth of hepatocytes in collagen gel or mixed culture with nonparenchymal liver cells.
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A very strong electroosmotic counterflow was produced on nitrocellulose membranes during isotachophoresis in a system of 0.06 M Tris-HCl (pH 6.7) as the leading electrolyte and 0.012 M Tris-beta-alanine (pII 8.6) as the terminating one. This counterflow was equal in rate and opposite in direction to the migration of the Cl-/beta-alanine boundary. The rate of counterflow was much higher than the rate of migration of any organic anions, including different proteins. Double-stranded and single-stranded DNA or its adducts were fixed on the nitrocellulose membrane, and the membrane was blocked with unrelated proteins. DNA-binding proteins, namely antibodies to DNA, followed by peroxidase-conjugated anti-IgG, were introduced into the counterflow, which transferred them one after another to the DNA spots. Thus, sequential binding and washing was performed automatically. In this way, antibodies were detected to ds- and ss-DNA, to BrdU-DNA, to Z-DNA, to biotinylated DNA and DNA modified with trans-Pt, as well as development of biotinylated DNA dots by steptavidin-peroxidase.
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