Perspectives in Biology and Medicine

CELLULAR COMMUNICATION, CONTACTINHIBITION, CELL CLOCKS, AND CANCER: THE IMPACT OF THE WORK AND IDEAS OF W. R. LOEWENSTEIN* ALAN C. BURTONi; Introduction Theexcuseforthis essaymustbe that itis oftenpossibleforthe onlooker to see more ofthe game than the players, for I have no research experience inthistopic, norhave Imade any significantcontributions. The ideas come from a far-from-thorough reading ofmany books, articles, and papers on cell growth and proliferation in tissue culture, and particularly from reading and hearing about the discoveries ofLoewenstein and his colleagues [1-9], on the communication between cells that form "tight junctions" when organized in tissue. I have also had the benefit ofdiscussions with local cancer research workers. The exciting finding of Loewenstein is that, while normal liver cells (and other types of normal cells) exchange substances of quite high molecularweightfromcellto cell, incontrastfivetypes oflivertumorcells proved to have very little communication between cells in contact [1, 2]. The lack of communication has been shown for other cancer cells [6], Naturally, one wonders ifthis could be a general distinction between cancer and normal cells, and how lack of communication of tumor cells in tissue could explain their uncontrolled proliferation, while communication between normal cells when "differentiated" and organized in tissue somehow inhibited their continued proliferation. Loewenstein himself [8] has suggested how communication could result in inhibition. I found the set ofideas to which I was forced by logic so exciting, and the implications in * This paper was accepted for publicationJune I, 1970. t Department of Biophysics, University of Western Ontario, London 72, Ontario, Canada. I am most grateful to Dr. Peter B. Canham, ofour department, for programming the computer studies; to Drs. W. R. Inch and R. M. Sutherland, my local consultants in radiobiology, for helpful comments and encouragement; and to Mr. Alfred Jay, to whom ideograms are familiar since he was brought up in Hong Kong, for drawing figure 1. 3OI suggesting new lines ofresearch so great, that publication here seems appropriate , in spite ofthe possible charges ofplagiarism. I doubt ifany of the ideas are really new to those who are engaged in relevant research, but not all ofmy own implications have been emphasized. After all, ifa set of ideas, linked by logic into a "theory," results in new kinds ofexperiments, even ifthe new results prove to contradict the theory, some contribution to science has been made. General versus Particular Properties ofCancer Cells In view ofthe high priority for some ofthe best scientific minds, most advanced techniques, and resources ofmoney and equipment, cancer research has hardly matched reasonable expectations. Perhaps the fact that cancer is not one problem, but a group ofheterogenous problems has led to such a high degree of specialization in cancer research, that we are "missing the woods for the trees." Most laboratories devoted to cancer research tend to put all their eggs in one or two baskets—for example, virology, cellular biochemistry, genetics, or the effects of radiation. It is difficult in the recent literature to find any discussions ofthegeneral problem ofcancer, whereas thirty years ago there were many articles and books on this topic. What is the general description of cancer cells compared with normal cells?, As a pathologist, Steiner [io] put it: "Cancer consists of a self-uncontrolled proliferation of the body's altered cells . . . whereas normal cell division for normal replacement, repair, hyperplasia and regeneration are strictly regulated according to the need." The emphasis ofa pathologist is (naturally) on the transformation from normal to pathological cells, and on intracellular rather than intercellular factors. I find a different emphasis in the essays of Albert Fischer [n], the pioneer in tissue culture. He was impressed by the persistent power of normal cells to proliferate when dissociated by migration or isolation from their fellows. He showed how, in a tissue culture, the mitotic rate in the central part ofa "clone" of cells in contact with each other was much less than in the "growth zone" at the periphery, and this ofcourse is now well known. He also noted the "interplasmic connections between the cells in contact," and thought them necessary for "differentiation" and cell structure. It apparently did not occur to him that these connections could play a role in inhibiting cell division in organized tissue...