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Clonal Variation in the Production of Tumor-associated ₂-Macroglobulin in a Malignant Human Melanoma and Association with Growth Stimulation¹

J. Bízik, A. Lizo^nová, M. Grófová², J. Matoka, J. F. Doré, S. Bertrand, M. Blako and A. Vaheri

Cancer Research Institute of the Slovak Academy of Sciences [J. B., A. L., M. G., J. M., M. B.], 81232 Bratislava, Czechoslovakia; Laboratoire d'Immunologie et de Cancérologie Expérimentale [J. F. D., S. B., J. B.], Inserum U 218, Centre Léon Bérard, 69373 Lyon, France; and Department of Virology, University of Helsinki [A. V.], 00290 Helsinki, Finland

₂-Macroglobulin (₂-M) is known as a wide-spectrum proteinase inhibitor and to bind covalently certain growth factors. We have previously characterized tumor-associated ₂-M synthesized and secreted by human tumor cell lines. Of the cell lines studied, the melanoma cell line HMB-2 produced the largest amount of this glycoprotein. Immunofluorescence staining of cultured HMB-2 cells suggested that the cell population is heterogeneous with respect to ₂-M production. We have now isolated clones from the parental HMB-2 cells and characterized eight representative ones in detail. They varied considerably in the quantity of ₂-M secreted, from 4.2 to 46.5% of total protein. No relationship between the production of ₂-M by these clones and their pigmentation or tumorigenicity in nude mice was found. However, statistically there was a strong correlation between the modal chromosome number and population doubling time (r² = 0.88, P < 0.001) and also between the modal chromosome number and ₂-M production (r₂ = 0.73, P < 0.01). The growth rate of the clones correlated with the level of ₂-M in culture medium (r² = 0.69, P < 0.01). Clones with lower ₂-M production had a proportionally shorter population doubling time than the clones with intermediate or high production. Northern hybridization indicated quantitative variation in the ₂-M mRNA expressed by the parental cells and the clones, that was comparable but not identical with the quantity of ₂-M in the respective culture media; both parental cells and clones expressed platelet-derived growth factor A-chain mRNAs with little difference in levels. Serum-free medium from low ₂-M producer clones stimulated normal stationary fibroblasts significantly more than clones producing intermediate or high amounts of ₂-M. ₂-M decreased and anti-₂-M IgG increased the stimulation. These results suggest that production of tumor-associated ₂-M is related to both autocrine and paracrine growth-stimulating activity of the tumor cells.

¹ The project was supported by funds partly provided by the International Cancer Research Data Bank Program of the National Cancer Institute, NIH (US), under Contract N01-CO-65341 (International Cancer Research Technology Transfer-ICRETT), and partly by the International Union against Cancer; and funds from the Association pour la Recherche sur de Cancer, Villejuif, France.

² To whom requests for reprints should be addressed, at the Cancer Research Institute, Cs. armády 21, 81232 Bratislava, Czechoslovakia.

Received 4/14/88. Revised 8/ 9/88. Accepted 11/11/88.