Intercellular Communication and Tissue Growth

Abstract

A B S T R A C TIntercellular communication was examined with intracellular electrical techniques in prim a r / a n d transplanted rat liver cancers. Normal liver cells communicate rather freely with each other through permeable junctional membranes. Cancer liver cells show no communication at all; their surface membrane is a strong barrier to diffusion all around the cell.Cancer cells induce alterations in membrane permeability in normal liver ceils; communication among the latter is markedly reduced when cancer cells grow near them. I N T R O D U C T I O NEvidence for direct cell-to-cell communication is now availablc for a wide variety of epithelial tissues (12, 12 a, 17). At the surfaces of cell contact (junctional surfaces), the cell membranes in, at least, some of these tissues are normally so permeable that many cellular substances may diffuse rather freely from one cell interior to the next. The present series of papers deals with the question of whether cellular communication of this sort is involved in the control of tissue growth.It has long been evident that normal growth of tissues depends on some form of contact interaction between cells. Harmonious growth requires, among other things, that cells recognize each other and stop moving and growing atthe right place. Instructive, in this respect, is the movement of epidermal cells over a wound; the movement stops when the cells meet (10). Particularly instructive is the behavior of cells in tissue culture growing on glass surfaces. The cells stop moving and dividing when they establish contact with each other, and stop only then (1, 24). Some kind of signal appears to be transmitted from cell to cell upon contact. The question here, then, is whether diffusion of substances from cell interior to cell interior is involved in the signal transmission.A direct approach to the question seems hopeless until specific signal substances are identified. But one may try an indirect approach and see whether cellular communication is altered in situations of uncontrolled cellular growth. Here, we shall explore this point in cells showing the most notorious lack of growth control, cancer cells. Cancer cells, unlike normal ones, neither stop moving nor dividing upon cellular contact, as is seen particularly clearly in tissue culture (2, 5-7, 23a).

Biophysical characterization of gap-junction channels in HeLa cells

“…Figure 2 gives an example of such an experiment, where the injected current pulse resulted in a depolarizing pulse superimposed to the membrane potential only in the injected but not in an adjacent cell. With inserted glass microelectrodes the input resistance of the cells is of the order of 10 Ms [10] ; together with the minimum coupling coefficient [11] of 0.01 the predicted resolution of the junctional conductance is about 1 nS. With high-resolution patch-clamp current recordings, junctional conductances exceeding this value have been observed only in 4% of the cases.…”

“…KCl-filled glass capillaries were used to measure ionic coupling between monolayer cells with three intracellularly inserted electrodes [10,11]. These measurements were performed under phase-contrast microscopes and the microelectrodes were operated by micromanipulators with electrical drives (DC3 + STM3, Gebr.…”

Modulation of cell communication and carcinogenesis.

“…Investigation of cell communication in cancer cells was first made in rat liver tumors including primary, Morris and Novikoff hepatomas by electrophysiological methods [35]. Subsequently, similar studies were performed in transplanted rat and hamster thyroid tumors [24] and human stomach carcinoma [28].…”

Relation between ionic coupling and morphology of established cells in culture

“…The communication ratio V,,/V,, as de-fined by Loewenstein & Kanno [22], namely the ratio of the voltage change at constant current pulses in the coupled cell to the voltage change in the cell containing both recording and stimulating electrodes, could vary between 0.3 and 1 .O but was independent of the cell density of the monolayer. Over a distance of more than 10 cells, the communication ratio was frequently found to be as high as between neighbouring cells.…”

“…Initial findings of Loewenstein & Kanno [22] with liver and hepatomas in situ revealed a difference between normal cells which showed ionic coupling and malignant cells which were not coupled. Subsequently, a number of in vivo and in vitro cell lines were described which were both malignant and ionically coupled [5,6,13,17,18,19,391.…”