The Control of Cell Division : A Review II. Special Mechanisms M. M. S WANN (Department of Zoology, University of Edinburgh, Edinburgh, Scotland) CONTENTS VIII. General discussion I. Introduction IX. The control of cell division and the cancer problem II. Differentiation and division 1. The metabolic pattern of cancer cells 1. The antagonism between differentiation and division 2. The fundamental basis of autonomy 2. The status of the growth and division mechanisms in differentiated cells I. INTRODUCTION a. Growth In the first part of this review (212), I attempted b. DNA c. Other division mechanisms to define a number of mechanisms that appear d. Discussion to be important in the initiation of division in 3. Division and growth as a form of differentiation a wide range of cell types. In this, the second 4. The differentiation problem part of the review, I shall consider to what extent 5. Further evidence on division and growth as a form these mechanisms are modified, and to what extent of differentiation 6. Conclusions further controls are imposed upon them in com munities of cells, particularly the tissues and or III. Vertebrate hormones 1. Bullough's in vitro experiments gans of higher animals. 2. Other in vitro work Within an organism, the majority of cells are 3. In vivoobservations specialized for various purposes and divide only 4. Long and short latent period responses to different infrequently. In Section II, I shall start by dis hormones cussing this antagonism between differentiation 5. The mode of action of the mitogenic hormones 6. Conclusions and division. There is some evidence that differ entiated cells have more or less completely sus IV. Control of growth in embryo and adult pended the various division mechanisms discussed 1. Compensatory hypertrophy and similar systems a. Liver in Part I; if so, the stimulation of such cells to b. Other organs and tissues divide must involve switching their synthetic ma c. The humoral feed-back type of control chinery away from making the products of differ 2. Skin wounds and limb regeneration entiation and over to making the various struc 3. Miscellaneous factors involved in the control of tural and enzymic proteins required for division. growth 4. The mode of action of regenerative and other growth One of the most important of these elements, stimuli and certainly the bulkiest, is the special protein 5. Conclusions required for the mitotic apparatus. It follows V. Plant hormones that division is best regarded as simply another 1. Auxins and kinins form of differentiation, there being no difference 2. Discussion and conclusions in principle between making proteins for some VI. Natural mitotic synchrony specialized function and making proteins for cell 1. Synchrony in syneytia division. 2. Meiotic synchrony Switches of synthetic pattern occur at intervals 3. Synchrony in cleaving eggs throughout development, being brought about 4. Mitotic rhythms in cultures of microorganisms by "induction." Having considered the nature 5. Mitotic rhythms in higher animals 6. Conclusions of this process, I shall turn to an examination of various lines of evidence which suggest that VII. Cell contact and cell division 1. Cell contact and the inhibition of proliferation the stimulation of differentiated cells to division 2. Conclusions may, in fact, be brought about in a similar way. 1118 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1958 American Association for Cancer Research. SWANN—ControlofCell Division: A Review 1119 In Section III, I shall review the problem of II. DIFFERENTIATION AND DIVISION those vertebrate hormones that stimulate cell di 1. THE ANTAGONISMBETWEENDIFFEREN vision. Although, no doubt, some of them exert TIATIONANDDIVISION effects on one or more of the division mechanisms It has long been realized that differentiated discussed in Part I, I believe that their most cells tend not to divide and that dividing cells important effect is more fundamental. It seems tend not to be differentiated. Waymouth (234) likely that they act inductively to switch the has assembled a large number of observations whole pattern of synthesis of differentiated cells and comments on this point; few people, however, over toward the making of protein for the mitotic seem to have considered why it should be so. apparatus and enzymes for a variety of other In spite of this antagonism, differentiated cells division mechanisms. are certainly capable of dividing. An embryo does In Section IV, I shall consider the control not consist of primordial undifferentiated cells, of growth in whole animals, particularly in con numbers of which, from time to time, differentiate nection with regeneration in its various forms. in various directions and then cease to proliferate. Here we have a situation where the recognized We can recognize in vertebrate tissue culture vari hormones are of minor importance, but where ous distinct cell types, all of which divide and substances, sometimes humoral, sometimes local, grow rapidly. Moreover, every tissue in the body are nevertheless involved. There is, moreover, of a higher animal shows at least occasional mi reason to think that, like hormones, these sub toses, with only two important exceptions: nerve stances act inductively to switch the pattern of cells1 and striated muscle. In the epidermis, in synthesis in a new direction. the gut lining, and in the blood-forming tissues, Sections II, III, and IV cover, I believe, the mitosis is very frequent, though the cells in ques most important aspects of the control of division tion might legitimately be regarded as not fully in higher animals, but there remain a number differentiated. However, even in obviously dif of other matters to be considered. In Section V, ferentiated tissues such as liver, kidney, and a I shall consider briefly to what extent plant growth hormones may act in the same way as the mito- whole range of glands, a few mitoses can always be found. Here again it is arguable that we are genie animal hormones. In Section VI, I shall dealing with undifferentiated reserve cells, though discuss natural mitotic synchrony; and in Section such evidence as there is suggests that these divid VII, I shall raise a few points which suggest ing cells are in various degrees differentiated (57). that cell division is in some way affected by However this may be, the differentiated cells, cell contact. I had originally intended to review except once again nerve and striated muscle, are also the questions of inhibition and stimulation certainly capable of dividing. Almost every cell inherent in gametogenesis, fertilization, diapause, in a regenerating liver, for instance, may undergo and dormancy. I believe, however, that the mech mitosis within a few days, and yet there seems anisms concerned are probably different from those to be little if any interruption of their normal employed elsewhere in higher organisms, and, since function (104). space is short, I have decided to leave out a dis The most that we can say about the antagonism cussion of these interesting, but rather specialized, of division and differentiation, therefore, is that problems. the more clearly differentiated a cell is, the less Summarizing the facts and arguments of this likely it is to divide, though, with the exception review presents certain difficulties, and rather of nerve and muscle, this capacity is never lost than adding a very long summary at the end irretrievably. I shall include a brief summary of conclusions at the end of each section. In Section VIII, 2. THE STATUSOFTHEGROWTHANDDIVISION however, I shall discuss the whole problem of MECHANISMSINDIFFERENTIATEDCELLS control in general terms. a. Growth.—In the first part of this review, Finally, by way of an appendix, I shall consider we saw that a certain minimum of growth was in Section IX the relevance of some of my con an essential prerequisite for division, though we clusions to the problems of cancer research. I did not inquire into the precise nature of this have deliberately restricted the discussion in this growth. However, there is no particular reason section to two matters, and I claim no particular to suppose that any type of increase in dry weight originality for my remarks. I hope, however, that will serve. Indeed, in the next section I shall they may add a little to some of the speculations 1Even differentiated neurons may in fact sometimes divide of others before me. (84, 158). Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1958 American Association for Cancer Research. 1120 Cancer Research Vol. 18, November, 1958 argue, following Mazia (150), that this essential is good reason to believe that this is owing to the minimum of growth may very well have to be presence of tetraploid and octaploid cells, as well synthesis of special protein for the mitotic figure as diploid ones, rather than to the presence of and other division mechanisms. Mere considera a large number of cells that have doubled their tion of the size of differentiated cells, therefore, DNA prior to mitosis. is not necessarily very illuminating and may give The evidence, then, indicates that most dif us no idea whether the essential type of growth ferentiated cells have not doubled their DNA has or has not taken place and whether, in conse and are held back or very much slowed down quence, differentiated cells are held in check by at some earlier point in interphase. The fact virtue of the growth mechanism or something else. that, as with growth, DNA in differentiated cells Some differentiated cells are certainly much does not double until a day or more after a hor larger than the undifferentiated cells that gave monal or regenerative stimulus suggests, moreover, rise to them—in particular, nerve and striated that the DNA mechanism is held up at some muscle cells; but these are, in fact, the cells that very miwh earlier stage (Sections III, 5; IV, 4).