Plasminogen Activators of Normal and Transformed Cells

Abstract

Cell surfaces of neoplastic cells have been the focus of the efforts of a number of laboratories in recent years [1]. The altered aspects of the neoplastic membrane have been extensively studied by chemical, physical, physiological, immu-nochemical and immunological approaches. One such area of investigation that has received considerable attention is the increased sensitivity of transformed cells to agglutination by certain plant lectins [1, 2]. These lectins, especially the agglu-tinin isolated from wheat germ [3] and Concanavalin A [4] isolated from jack bean meal, appear to react with carbohydrate determinants on the cell surface. Presumably, the enhanced agglutinability of cells transformed by oncogenic viruses results from an increase in the number of agglutinin binding sites at the cell surface, an alteration in their distribution, or other as yet undefined alterations in the molecular structure of the membrane. Changes in agglutinability, found during transformation or reversion of transformed cell lines to a morphologically normal state, usually are paralleled by changes in growth properties. Tt has been suggested by Burger that the surface alterations detected by the change in agglutinability are necessary for the alterations in growth properties following viral transformation. In fact, brief incubation with low concentrations of proteases can cause normal cells, which have been contact arrested both in growth and movement, to overgrow and to become agglutinable [5, 6]. Escape from density-dependent inhibition appears to be mediated via a cell surface phenomenon since insolubilized trypsin on beads, which are not phagocytosed, has the same effect as soluble trypsin. It is not certain whether the release from density-dependent inhibition of growth by proteases and by serum [7] occur by similar mechanisms. Serum stimulation of growth is most probably related to the overgrowth-stimulating activity reported by RUBIN [8] and recently confirmed in this laboratory [9]. Schnebli and Burger [10] have demonstrated that incubation of transformed cells with inhibitors of proteases causes those cells to grow to saturation densities similar to those observed for normal cells. The corollary of this observation is that transformed cells incubated with a protease inhibitor should become markedly less agglutinable. Recent experiments in this laboratory have substantiated this prediction [9, 11].

Supported by research grants CA 13362 from the National Cancer Institute and AI-05600 from the National Institute of Allergy and Infectious Diseases, and a Brown-Hazen grant from The Research Corporation.