TISSUE GROWTH AND TUMOR GROWTH’ LEO LOEB From the Department of Comparative Pathology, Washington University Medical School, St. Louis Received for publication February 16, 1917 Tumors in general and cancers in particular are tissues growing under special conditions. A comparison between the laws de- termining tumor and tissue growth will deepen our knowledge of the physiology of tumors as well as of tissues. There exist similarities and analogies in the behavior of both, and there are differences either real or due to a gap in our knowledge. The differences will suggest new problems. In this brief r6sum6 no attempt at completeness will be made, and we will have to be content with mentioning some of the salient points. We shall first compare the causes of tumor and tissue growth, then the reactions of the host organism against tumor and tissue growth, and lastly, certain phenomena observed primarily in the tumor cells. We will have to inquire how far the last mentioned phenomena are duplicated in tissue growth. 1. Tissue growth is initiated by external factors affecting a more or less complicated system and leading to chains of reac- tion which may be identical, or at least similar, even in ‘casesin which the primary causes differ. These primary causes are called “formative stimuli’’ in order to distinguish them from functional stimuli. It is probable that essentially both kinds of stimuli are identical and act in a similar manner. The dif- ference in the result of both kinds of stimulation depends prob- ably on the quantitative differences in strength and time, and on the differences in the systems on which they act. 2. The primary causes initiating tissue growth may be either 1 Read in a symposium on cancer before the Section of Experimental Medi- cine of the American Association for the Advancement of Science in New York, December 29, 1916. 136 136 LEO LOEB physical or chemical. The physical factors are either mechani- cal or rays which are held back by the tissues. The chemical ones are essentially substances produced somewhere in the or- ganism. Certain parasitic organisms which cause tissue and tumor growth act partly through chemical agencies which they produce; they may in addition exert a mechanical effect. In re- gard to substances produced outside of the organism and caus- ing local tissue growth after application to certain tissues, it is doubtful how much their action is a specific chemical one and how much it is due to secondary physical factors released through injury of the tissues. Some pathologists assumed mechanical factors to be the only ones which can elicit tissue growth under experimental or pathological conditions. This view is evidently erroneous. Pathological or experimental phenomena are merely a modified interaction of phenomena occurring in the normal life of the organism. Chemical stimuli undoubtedly play a consid- erable part in the normal growth phenomena of the organism. This alone is presumptive evidence that they have a similar function under pathological conditions. 3. It can be shown that the stimulus brings about a series of changes in the affected tissue; these changes are partly chemical, as evidenced by increased oxidation, or physical (increased water content of the cells). They lead to a greater. sensitiveness of the cells. Corresponding to their chemical and physical changes, morphological changes take place. These changes follow a defi- nite curve. A new stimulus reaching the cell after a certain stage of this curve has been reached acts therefore on a dif- ferent system and must produce different results. It has been shown that small quantities of various rays acting on various tissues may produce stimulation, while large quantities cause destruction. In conjunction with Doctor Spain we have shown that larger defects may produce a more energetic response of tissues than smaller defects; they represent a stronger formative stimulus. Successive formative stimuli lead only to a limited extent to increased reaction. Adaptive tissue changes imply- ing an increased resistance to the stimulus are called forth. Thus a limitation in the proliferative effect is produced. TISSUE GROWTH AND TUMOR GROWTH 137 4. If a strong growth stimulus affects tissues under otherwise unfavorable conditions, as for instance at a place where the sup- ply of food and oxygen is diminished, an abnormal response of the tissues takes place (irregular mitoses, amitotic nuclear di- visions, formation of giant cells and syncytia) . If the conditions of nourishment become still more unfavorable, necrosis follows. Quite generally growth stimuli more or less inhibit the full morphological differentiation and correspondingly the full meta- bolic correlative activity of tissues. This effect finds expression in a simpler structure of various growing tissues. The facts mentioned under No. 3 and No. 4 apply on the whole equally to normal tissues and tumors, but they are usually more marked in the case of tumors, especially cancers, because here either the growth stimuli are stronger or the conditions of growth are more irregular and therefore more unfavorable as far as nourishment is concerned. 5. These same physical factors, the formative stimuli for tissue growth, when acting over a long period of time, lead in certain individuals to the production of tumors or cancers. It has been possible to produce cancers experimentally through the appli- cation of physical or physico-chemical factors (P. Marie, Fi- biger) . These experimental facts correspond to observations in human cancer. Apparently the transformation from normal tissue to cancer is a gradual one, passing through several inter- mediate steps. However, if we work with either normal tissues or cancers or intermediate formations (regenerating tissue, in- flammatory new-formation, benign tumors), in most cases they retain their original characteristics in a fairly constant manner during the period of experimentation. 6. Formative stimuli of a mechanical nature act on certain cancers as they do on normal tissues. Cuts, incomplete extir- pation, pulling threads through tumors that have become sta- tionary, transplantation of tumors, act as stimulants and increase the energy of growth. 7. Chemical formative stimuli undoubtedly play a consider- able r81e in the growth of normal tissues. From the data which are accumulating, it may be possible in a provisional way to 138 .LEO LOEB classify these chemical stimuli into (a) general stimuli, applying indiscriminately to a large number of tissues; (b) specific stimuli acting only on specific tissues. Chemical factors of the former kind are probably operative in young organisms, in contradis- tinction to old ones, and during pregnancy. In the last named condition not only factors favoring growth are apparently at work, but also factors antagonistic to growth. The balancing between these two forces seems to lead to a different result in different species. Thus in the rat, pregnancy seems to favor growth of embryonal tissues under certain conditions; in the mouse, it is unfavorable to such growth. Tumor growth is affected in a way similar to normal tissues by the chemical con- ditions prevailing in young and old organisms respectively. The difference in the growth of certain organs in young and old animals seems to depend on substances circulating in the body fluids. Analogous substances seem to hasten or to delay growth phenomena associated with metamorphosis in amphibia. There is also some indication that during pregnancy spontaneous tu- mors may assume a marked increase in size in the rat, while in the mouse, pregnancy is an unfavorable factor, especially for the growth of transplanted tumors. In future it will be necessary to distinguish more sharply than has been done in the past be- tween the effect of pregnancy on the growth of spontaneous and of transplanted tumors. The corpus luteum, which stands in specific relation to the wall of the uterus and perhaps to the mammary gland, is an example of the second kind of growth substances. There can be no doubt that these specific growth substances play an important r81e also in the transformation of normal into cancerous tissues. This has been proven experimentally by the writer in the case of the cancer of the mammary gland in mice. By extirpation of the ovaries at the time maturity has been reached, the spon- taneous development of cancer of the breast, which is so common in certain strains of mice, can be almost altogether prevented. We may assume that other specific correlative growth substances play a similar part in the cancerous transformation of other tissues, TISSUE GROWTH AND TUMOR GROWTH 139 There is another class of growth substances, namely those which prevent growth and the absence of which promotes growth. We might call those: “negative growth substances.” We might include iodine in ths category which, according to Marine, prevents compensatory hypertrophy of the thyroid. In a simi- lar manner, ttccording to Raymond Pearl, calcium seems to counteract certain of the actions of the corpus luteum substances; but whether it inhibits the growth processes called forth by the corpus luteum, has not yet been investigated.2 There is, how- ever, some indication that calcium inhibits somewhat the growth of inoculated tumors, although it is not certain that the evidence in this direction is conclusive. 8. -There are cases in which a chemical and physical stimulus must cooperate in order to induce considerable tissue growth. The formation of the maternal placenta is an example of this kind of growth. A definite relationship exists in this case be- tween the chemical and physical stimulus. The chemical stimu- lus has to precede the physical (mechanical) stimulus. It sensitizes the tissues to the action of the physical stimulus. However, in order to obtain the fullest possible growth re- action, the chemical stimulus must continue to act after the onset of the physical reaction chain. A similar combination be- tween chemical and physical stimuli seems to play a part in plant growth, as has recently been‘ discovered by Haberlandt.