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Chemical Digest
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WARBURG REPORT ON THE METABOLISM OF TUMORS Professor Otto Warburg,' of the Kaiser Wilhelm Institut fiir Biologie, Berlin-Dahlem, has, in a monograph2 recently published, recorded and interpreted the findings in his laboratory concerning the metabolism of tumors. A brief summary of this report has been prepared for THIS JOURNAL by Dr. Charles F. Geschickter, Garvan Cancer Research Laboratories of The Johns Hopkins Hospital and University, Baltimore, Maryland. The twelve important points brought out by Professor Warburg are as follows: I.
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Because of finding a high rate of oxidation in the sea-urchin's egg a t a period of maximum growth, Warburg thought this high oxidation would be true of cancer tissue. However, it was found that cancer consumed oxygen a t the same rate as normal liver and kidney tissue, and that its growth energy depended on a second form of metabolism, splitting glucose t o lactic a d d (called glycolysis). Cancer tissue is like the lactic acid bacillus, it lives partly by oxidation and partly by glycolysis. Cancer tissue forms 10 t o 12% of its own weight of lactic acid per hour. Glycolysis cannot be compared t o the ferments of the lipases or proteolysins because these latter fermentations are not enerm -~ producinz. That glycolysis produces tumor energy is shown by the fact that tumor tissue will live in sumr solutions in an absence of oxygen, but will die and not be transplmtable if oryvcn and sugar are hntrahsent.~ Pnstrur was t h e first to show that glywlysis is reduced by the presence of oxygm. and Meyerhoff was the &t t o show this effect as a measurable constant, showing that one molecule of oxygen caused from one t o two molecules of lactic acid t o disappear. The most important finding in regard t o tumor metabolism is that although the anaerobic glycolysis or sugar splitting of the tumor tissue is reduced in the presence of oxygen, the tumor breathing rate in comparison with the glycolysis rate is too small t o prevent the sugar splitting from going on. Quantitatively in the presence of air, tumor tissue bums only one molecule of sugar with oxygen, while twelve molecules of sugar are being split by glycolysis. Malignant tumors of the rat and Raus sarcoma, human cancers of the skin, mucous membranes, and glands all show this same constant property of sugar splitting in the presence of oxygen. Benign human tumors of both epithelia and connective tissues were shown to resemble malignant tumors in their metabolism, Mering from cancers only ~
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Prof. Warburg recently made an address on "Iron as a Catalyst in Biological Oxidation" before the Johns Hopkins Hospital and Medical School under the auspices of the Huerter Foundation Lecture. "Uber den Stoffwechsel der Tumoren," Julius Springer, Berlin. Germany, 1926, 266 pp., $4.50. 179
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JOURNAL OF CHEMICAL EDUCATION
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1930
in degree. Benign tumors have a high glycolysis (sugar splitting with lactic acid formation) in the absence of oxygen, just like malignant tumors, hut aerobically glycolysis in the benign tumor is reduced t o one-third or one-quarter that of malignant tumors. VII. Embryo tissues fall in line with benign and malignant tissues having a high anaerobic glycolysis. Thus a high anaerobic glycolysis can be considered a characteristic of all rapidly growing tissues. But the embryonic tissues in the presence of oxygen cease totally their glycolytic activity, thus showing that the difference hetween unorderly gmwth and orderly growth is a question of aerobic -. ~lvcolvsis. VIII. On the basis of the findings above (in VII) the following hypothesis is postulated as the cause of tumor origin. The small amount of glycolysis present in normal tissue is supposed t o w i d e in certain embryonic cells scattered through all normal tissue. When the oxygen want rises through sclerosis of vessels or inflammation the normal cell&are killed off and only the embryonic cells capable of living anaerobically in the absence of oxygen by glycolysis continue to multiply. ifthe oxygen want is chronic the cells become adapted by having a high glycolytic metabolism and a low breathing rate and they constitute the malignant growth. (Warburg does not state why their growth should be so disorderly, but Biericb has shown that the lactic acid formed breaks down normal connective tissue boundaries.) That glycolysis should be a property of all normal tissues not in a state of comIX. plete rest, follows if such metabolism is a property of growth. I n keeping with this all normal tissue was found t o have some glycolysis, and young epithelium more than old. Although it is true for tissues that there is no growth without glycolysis, the X. reverse, no glycolysis without growth, is not true. The retina shows high aerobic and anaerobic glycolysis. We account for this exception by saying that the retina is particularly vascular in vivo, and has a high enough oxidation rate t o suppress glycolysis, but experimentally we deprive i t of this blwd supply, I. etc. The relation of tissue growth to cancer can be conceived in terms of glycolysis XI. and metabolism as follows. At first embryonic tissue exists with a high anaerobic glycolysis and a high aerobic respiration. Then the tissue comes to an adult resting with a low anaerobic glycolysis and a comparatively high oxygen .phase . respiration. From this stationary condition, carcinoma develops by a reversion t o the embryonic f m of metabolism, with a high anaerobic glycolysis, without the rate of oxygen respiration following suit. XII. The w x of these findings are summed up in this fashion: "The metabolism of the cancer cell is a balance made up of glycolysis and oxidation. just as the metabolism of the aerobic lactic acid b a d u s is. The cancer tissue is differentiated from embryonic tissue, resting and growing epithelium whose metabolism is f,undamentally an oxidation process by the preponderantly glycolytic nature of its -~~metabolism. "Quantitatively and qualitatively the glycolytic metabolism of cancer is not different from the alvcolytic of embryonic metabolism, but because in .. . phase . cancer metabolism the balance between glycolysis and oxidation is disturbed in favor of glycolysis, glycolysis appears greater." ~~
