Contact-dependent inhibition of growth of normal diploid human fibroblasts by plasma membrane glycoproteins.

Homeostasis in vivo is maintained by a highly complex network of positive and negative signals. At the cellular level, this regulatory microenvironment can be divided, in a simplified fashion, into two major compartments: the humoral compartment, including compounds such as hormones, growth factors and nutrients, and the contact-environment compartment, including cell-cell and cell-matrix interactions. At least in cultures of diploid, non-transformed cells, cell-cell and cell-matrix interactions have been shown to be of major importance for the regulation of growth as well as of differentiation. Although until now the glycoprotein involved in the contact-dependent inhibition of growth has not been fully characterized, our studies give evidence for the involvement of a plasma membrane glycoprotein with an apparent molecular weight of approximately 80 kDa in the growth regulation of diploid human fibroblasts. The important characteristic of this glycoprotein is: the biologically active determinant resides in terminal, beta-glycosidically linked galactose residues on N-glycosidically linked glycans. From our studies, a receptor has to be postulated which, in addition to the galactose residues, has additional structural requirements for the specific binding of this glycoprotein, since other glycoproteins carrying terminal, beta-glycosidically linked galactose-residues are without biological activity. The postulated receptor is suggested to be defective in tumor cells, since these cells are no longer able to respond to cell-cell contacts with stopped proliferation, although they are able to inhibit growth of non-transformed cells. The inability of a tumor cell to recognize and to bind to the specific glycoprotein would result in a release from growth inhibition, leading to clonal growth of these cells. Further detailed studies on the structure and the regulation of the glycoprotein, as well as an attempt to isolate the postulated receptor, should lead to a better understanding of the complex pattern of growth regulation of normal cells.