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On a unifying concept of cancer
Life Sciences Vol . 3, pp . 917-928, 1964. Pergamon Press, Inc . Printed in the United States .
REVIEW ON A UNIFYING CONCEPT OF CANCER Leon Brody Director of Research, Center for Safety Education, New York University Washington Square, New York 3, N. Y. (Received 19 June 1964) An oxygen-stress-reaction theory is outlined as an umbrella for divergent views and isolated facts . IN cancer the spectrum of causation appears to be remarkably broad. There is a constant flow of studies purporting to relate the incidence of cancer to a great variety of factors, usually physical, chemical, or viral . As a result assertions have been made that cancer may actually involve a "family" or scores of diseases . The vexing situation is also reflected in the NationalCancer Institute's screening of tens of thousands of chemical compounds in the search for cures and controls . Not only are there divergent views as to types of cancer from a casual standpoint, but even with respect to a relatively definable type conflicting reports appear . Thus the recent issuance of the U. S. Public Health Survey link ing cigarette smoking and lung cancer, has been followed by a medical reportl that there is no statistical connection ; that air pollution by gasoline vehicles and industrial gases is a more likely cause of lung cancer . As a matter of fact, previous experimental studies have shown that the concentration of pollutants in ambient air may be sufficient to produce malignant transformations . Simi1 laxly, proponents of viral causation are confronted with reported evidence that cancers may readily be produced in rats and mice raised under presumably virus-f ree conditions. It seems obvious that a unifying concept of cancer would help to reduce confusion and accelerate progress . Such a concept is possible if common denominators can be located among various carcinogenetic processes or even deduced from düferent therapeutic measures that appear to have contributed in some degree to cancer management . One is encouraged at least to conjec917
91 8
ON A UNIFYII~TG CONCEPT OF CANCER
Vol . 3, No. 8
tore along these lines . Warburgs Theory and Some Implications There is reason to believe that a sound basis for a unifying concept is to be found in Otto Warburgs studies of cell metabolism, which now extend over a period of more than three decades . A cell needs oxygen to produce energy for survival and development ; in a sense it breathes . In this respect Warburg3 observed a dramatic difference between a cancer cell and a normal cell. Whereas a normal cell obtains most of its energy through respiration, a cancer cell depends largely on fermentation for its source of energy . It was presumed therefore, that cancer is initiated when the mechanism by which individual cells use oxygen (or breathe) is damaged. The cell-injuring agents range from radia.tfon to chemical compounds. For a period of time the cells continue to struggle with damaged respiratory mechanisms . Finally, to overcome their oxygen shortage, they resort to a new form of energy production -- fermentation . With fermentation oxygen is not necessary . However, fermentation is not as efficient as respiration . Under the former there is incomplete combustion of sugar, with lactic acid as the end product ; and cell components that normally would be used for growth and reproduction are utilized for energy production. While normal cells, which provide complete combustion of sugar (with carbon dioxide and water as end products), differentiate or organize themselves into normal tissue or organs, fermenting cells grow wild and form masses that may take possession of vital tissues and organs In view of this theory, what are known as "sleeping cancer cells" may well be cells that have been damaged but have not yet made the transition to fermentation, perhaps because the extent of injury is borderline (additiona.l stress may bring it to the critical point) or because the resistive or adaptive capacity of the cells is at a relatively high level. Cancer control, then, would need to take into account objectives of these kinds: (1) to maintain normal cell respiration ; (2) to prevent fermentation that has nothing to do with normal function (Warburg, in view of his findings con cerning the end product of fermentation, has suggested that inhibition of the enzyme forming lactic acid should prevent cancer cells from developing ; (3)
to restore the respiration process as soon as possible after injury of the cell . The latter, of course, assumes a reversibility of effects .
Vol . 3, No . 8
ON A UNIFYII~TG CONCEPT OF CANCER
91 9
In any case the common denominator or critical phenomenon in carcinogenesis may be hypothesized to reside in oxygen supply and utilization at the cellular level . Numerous tests of this hypothesis are possible .
The following
are illustrative : 1.
That high-pressure or high-level oxygenation is helpful in cancer control;
2.
That reduction of the oxygen requirements of tissues, within limits, tends to counteract stress reactions that interfere with normal metabolic functions;
3.
That there is a high incidence of cancer among aerobic organs and a low incidence in organs where oxygen is used efficiently ;
4.
That there is a greater incidence of cancer in the diabetic population, because hypoxia aggravates the metabolic difficulties associated with diabetes ;
5.
That malignant tumors may be frequent at high altitudes, where oxygen supply is reduced to functionally hypoxic levels .
Evidence or observations relating to these tests of the hypothesis may be categorized as follows . Hybaroxic Radiation Dramatic results are being reported for hyperbaric oxygen therapy in many conditions, ranging from arterial insufficiency to carbon monoxide poisoning and carcinoma . 4 It has been known for years that the effects of radiation are enhanced by increasing oxygen in the tissues at the time of irradiation; or conversely, that a cell deprived of oxygen is less sensitive to X-rays .
With
accumulating evidence that many or most of the cells in malignant tumors are anoxic or hypoxic, one has a logical base for explaining the greater success of cancer radiotherapy under hyperbaric oxygenation .
Oxygen breathed under two
or three atmospheres of pressure tends to saturate the blood and thus provide a higher level of oxygen even in the center of tumors, facilitating their destruction by irradiation.
In some individuals such procedure may entail oxygen
toxicity, possibly because C02 levels and tissue acidity are elevated, but various drugs are reported to be proving effective, experimentally, in affording protec tive action.
In any case the over-all evidence tends to affirm the first test of
the hypothesis of this paper .
920
ON A UNIFYII~TG CONCEPT OF CANCER
Vol . 3, No. 8
Regional Infusion with Hydrogen Peroxide This procedure is intimately related in concept, application, and effect to hybaroxic radiation, for the indications are that hydrogen peroxide irüusions
increase oxygenation within tumors and enhance tumor response to irradiation . 5 The beneficial activity of peroxides in attacking tumor cells was suggested by Warburg long ago .
Now, by regional perfusion, it is being found that high con-
centrations can be attained where particularly needed.
ù~jection into the blood
supply of the tumor makes for greater selectivity in destroying cancer cells by irradiation, with minimal damage to surrounding tissue. another technique is noteworthy : iontophoresis .
In this connection
The process of ionizing drugs
with an electric current so that they penetrate tissue is not new .
As a matter
of fact such experimentation with hydrogen peroxide was applied to tumors of rats thirty-five years ago at the Cancer Institute of the University of Berlin . This procedure is mentioned now because of its possible implications with regard to the discussion of ions later in this paper .
In any case, reported re-
sults with regional infusion of hydrogen peroxide again tend to support the first test of the stated hypothesis . Hypothermia, Hy~ometabolism, and Shock Surgeons have long been aware of advantages to be gained by lowering body temperatures during operations in which the circulation must be interrupted . The effect of hypothermia is to reduce oxygen requirements and consumption in the tissues, thereby lowering metabolism and cellular oxidation. for the subject of this paper immediately suggests itself ;
An implication
indeed, it is not too
surprising to note that more than one hundred years ago a method of body refrigeration was employed in an attempt to treat carcinoma . In recent times Laborit and othersg, combining hypothermia and drug complexes, have concerned themselves with artificially induced hibernation in man, somewhat similar to the condition of hibernating mammals and cold blooded animals .
Their objective: to calm disorganized reactions of the neuro-
endocrine system by effecting temporary aba~xionment a~f metabolic processes that tend to run counter to normal life function . Not only has such procedure proved valuable in surgery, it has also demonstrated effectiveness as an adjunct in protecting against consequences of trauma or shock and in treatment of cerebral hypoxia . As indicated by Laborit's work and elsewhere, hypometabolism may be
Vol . 3, No. 8
ON A UNIFYING CONCEPT OF CANCER
induced or potentiated by a number of drugs . has such an influence on nervous tissue .
921
Chlorpromazine, for example,
La.borit found the barbiturates par-
ticularly effective in connection with artificial hibernation because of their effect on cellular metabolism, in decreasing oxygen requirements .
The possible
significance of the latter fact is illustrated by evidence of enhanced tissue tolerance of high CO saturation of the blood . Thus, the second teat of the hypothesis of this paper seems to be further affirmed .
Of course, there is need for additional exploration of the relevance
of these concepts and procedures to the phenomena of cancer .
It is interesting
to note, however, that so-called "irreversible shock" (or stress) is considered to produce decreased tissue perfusion and utilization of oxygen and, at least in the case of hemorrhagic shock, causes a marked elevation in the blood concentrations of glucose and lactic acid, among other effects .
Significantly, these
alterations are characteristic of hypoxia and indeed appear to correspond with phenomena of cancer as previously set forth.
The question is inevitable : Is
there a parallel between stress reaction and cancer? More boldly, do they entail the the same dynamics, from initiation to outcome? ü so, within what limits, considering individual differences and tolerances, can hypometabolic measures be employed for purposes of prevention, control, and reversal? Miscellaneous Clinical and Statistical Considerations The three additional tests of this paper's hyposthesis relate to the following: (1) The incidence of cancer in aerobic organs and in organs where oxy gen is used efficiently . There is a dearth of dependable statistics in this area. However, data compiled by the New York State Bureau of Cancer Control for the period 195819ô0 8 indicate a particularly high incidence for the kidney, brain (and central nervous system), and liver (primary) . The kidney is an especially aerobic organ and therefore very susceptible to hypoxia . The subnormal levels of cerebral oxygen consumption in conditions ranging from senile psychosis to alcoholic coma are evidence of the brain's susceptibility to hypoxia . The significance of liver incidence of cancer probably derives from the fact that alcohol impairs the ability of tissues to utilize oxygen supplied by the blood stream . On the other hand, tumors of the heart are a medical rarity. 9 Although the heart gets only one tenth of the oxygen received by the entire body, no organ uses oxygen more
922
ON A UhTIFYII~iG CONCEPT OF CANCER
Vol . 3, No. 8
efficiently . Such data tend to affirm the third test of this paper's hypothesis . (2) ire incidence of cancer in the diabetic population. On the assumption that diabetics are subject to or exposed to hypoxiainducing conditions roughly to the degree applying to the general population, but because of the metabolic difficulties intrinsically associated with a condition where sugar is inadequately absorbed or utilized by body cells, it was subhypothesized that there would be a relatively high incidence of cancer among diabetics. Available facts seem to bear this out. Early datal0 show very substantial, positive correlations . This is supported by a more recent appraisalll attesting to the greater incidence of cancer in the diabetic population and observing that the relationship is becoming increasingly apparent as more diabetics live longer into the "cancer age" . It is noteworthy that in the majority of cases the onset of malignant disease reportedly occurs after the diabetes has been established . (3) The incidence of cancer at high altitudes . It has been believed that malignant tumors are not frequent in communities located at high altitudes . Presumably one of the principal reasons for this belief is the reduction in man-made air pollutants with increasing elevation . Al though there is some validity in the latter fact, it relates to a limitied casual concept, for another concomitant of high altitude is reduced oxygen supply . While natives and others tend to adjust to such hypoxic conditions, the fact remains that it is an adjustment to conditions that are more or less incompatible with inherent biological processes . Perhaps this reason helps to account for recent findings, 12 through autopsy and biopsy, that carcinoma of the cervix, skin melanomas, and gastric carcinomas occur frequently among residents of high-altitude communities . The Question of Viral Causation Numerous viruses are known to cause cancer in animals ; many scientists believe that viruses cause at least some human cancers ; no virus has yet been proved to cause human cancer . In the quest for a unifying concept there may be some significance in the mechanism of viral action. It is commonly thought that a virus will puncture a cell wall, injure the cytoplasm of the invaded cell, and disrupt nuclear function so that the cell turns from its normal activity to the production of new virus particles in the image of the invader (which then burst out to infect other cells) . In other words, because a virus is unable to reproduce by itself, it multiplies by using material and energy from ordinary human
Vol . 3, No. 8
ON A iTNIFYII~TG CONCEPT OF CANCER
92 3
cells . Again the hypothesized common denominator in cancer causation suggests itself : disturbance or destruction of the cellular processes of respiration and oxygen utilization. There may be supporting implications in relatively recent reportsl3 that viruses of a kind known to cause common respiratory illnesses in man, from colds to whooping cough and pneumonia, are also capable of causing cancer in animals . One is tempted to wonder whether such illnesses may represent incomplete, reversible "cancers" of the respiratory tract. More objectively, it is suggested that correlational studies of "cold proneness" and cancer incidence of related varieties would not be unwarranted . The Possible Role of Ionized Air Reference has previously been made to the fact that biologic systems are sensitized by oxygen to the effects of ionizing radiation and that this has some relevance to the reported usefulness of hybaroxic radiation therapy in the management of cancer . Air ions, which are produced by both man-made and natural radiation, may indeed have a broad role in the various phenomena of cancer, contributing to a unifying concept derivable from Warburgs theory and extended in the concluding section of this paper . Of primary significance is the indication that positive ions represent carbon dioxide molecules which have lost electrons, while negative ions represent oxygen molecules to which extra electrons have become attached as a result of a highly binding electron affinity . l4 Admittedly, there is much more speculation than evidence regarding the various effects of ionized air and the conditions under which they obtain. Within these limits certain interrelationships of fact and .opinion are suggested:l 5-19 (1) Tons entering the respiratory tract are repulsed or attracted, depending on the electric charge of the membranes . The
charge of the membranes of .alveolar cells is usually positive, enabling them to adsorb mainly negative ionic charges . This
tends to facilitate normal function. On the other hand, strongly concentrated,positively charged air has some of the same biological effects as shortage of oxygen and excess C02 in the blood . (2) Negative ions carried by the blood to body cells, according to Vasilyev, serve to restore the normal negative
ON A iTNIFYII~TG CONCEPT OF CANCER
924
Vol . 3, No. 8
charges of those cells - charges that are reduced by aging and disease - and tend to maintain normal metabolic processes. The mechanism of such action is said to be through an effect on the permeability of cell membranes and through desirable reaction with certain enzymes . (The latter, reportedly, may be deactivated or poisoned by positive ions. ) (3) It has also been indicated that negative ions stimulate the secretion of anti-inflammatory gluco-corticoids, while positive ions either inhibit this secretion or stimulate the secretion of inflammatory corticoids; and that under exposure to positively ionized air there is evidence of enhanced vulnerability of tissue to trauma, the converse applying in the case of negatively ionized air . With the reported affinity of oxygen and negative ion charges, there appears to be some rationale - within the scope of this paper's hypothesis for observations that negative air-ion therapy inhibits the development of
tumors in rats and mice. Such therapy, however, is impeded by the fact that under normal atmospheric conditions, high ion concentrations are difficult to achieve because of ion mobility and short life. On the other hand, this same fact may account at least in part for the relative effectiveness of hybaroxic procedures . With the currently high interest in the relationship between cigarette smoking and cancer, it is noteworthy that a charged-particle or ion hypothesis has been advanced20 as an alternative to the carcinogenic chemical concept (involving, for example, possible effects of tobacco tars) . There now is reason to believe that either approach is too limited. Thus one may point to the reported synergistic action of ionizing radiation and cigarette-smoke extracts, or other chemical agents, in experimental cancer production. 21
Finally, in view of the indications that negative ions enhance and positive
ions inhibit oxygen utilization, there appears to be justüication for expanded research on electrical properties of tumor cell surfaces (as compared to nor
mal cell surfaces) and on methods of alt Bring surface charges so as to attract negative ions and repel positive ions. The Involvement of DNA There has been increasing attention to the role of the deoxyribonucleic
Vol . 3, No. 8
ON A UNIFYII~TG CONCEPT OF CANCER
925
acids (DNA) that constitute the chromosomes of the cell, residing in the cell nucleus . 22 It is indicated that carcinogenic-related DNA changes occur when cells are damaged to the extent that certain of the normally vital cellular functions are impaired or eventually destroyed . Indeed there is a tendency to consider DNA changes as basic to the entire problem . But in the light of previously presented fact and theory, it is here proposed that DNA changes are better viewed as one of the critical characteristics or concomitants of the over-all carcinogenic process rather than as the primary definitive or causal aspect . Of course, when cell division is required, then the role of DNA assumes greater significance . But it is noteworthy that some DNA molecules apparently are not put to use in ordinary function and therefore may constitute some kind of reserve ; further, that there are mutations which may change a DNA molecule in such a way that the cell functions somewhat differently but does not die . Toward a Unifying Concept :
Recapitulation and Extension
It has been suggested in this paper that the common denominator or critical phenomenon in carcinogenesis resides in inadequacy of oxygen supply and utilization at the cellular level. This concept, crudely supported by facts and theory relating to specified sub-hypotheses and various prominent views on cancer, seemingly is applicable to an understanding of reported causation by numerous physical, chemical, and viral agents . These may all be considered in relation to stress and stress reaction involving cellular oxygen supply and utilization . ü so, the essential dynamics of carcinoma are reduced to relatively definable proportions . Selye's stress theory23 holds that many diseases have no single cause or specüic pathogen but are due largely to non-specific stress and pathogenic situations resulting from inappropriate responses to such non-specific stress . In other words, the stress phenomenon has its own characteristic form but no distinctively specific cause. This parallels the interpretation of cancer in the present paper . Further, Selye has emphasized that one of the principal "lessons" learned from thirty years of research on stress is that the body can meet very diverse aggressions (from irradiation to nervous tension) with the same adap tive defense mechanism .
His "general adaptation syndrome" specifies three
stages of response : (1) the "alarm reaction", when body systems are activated to counter the stress ; (2) resistance and adaptation, when a balance between
926
ON A UNIFYII~TG CONCEPT OF CANCER
Vol . 3, No. 8
stress and the host reaction is obtained ; (3) exhaustion, when defense processes break down and degeneration sets in. Again there is a parallel to the proposed concept of cancer, particularly as it reflects Warburgs theory. Damage to cellular machinery for utilization of oxygen (or interference with normal machinery function) tends to be followed by a struggle for survival and then, in many or most cases, by fermentation and normal cell destruction . The second stage seems to provide some rationale for observed delays in cancer development or what has been referred to as "sleeping cancer cells". Of course, most mammalian organisms seem to be constructed in such a way that they can deal with most everyday stress situations and emerge unharmed, or at least without irreparable damage to organs or tissues . Built-in regulatory and adaptive mechanisms apparently make possible a dynamic type of equilibrium or what may be termed "variable homeostasis", for a given individual . But individual differences in potential or actual tolerance do exist. For example, while all biologic systems are affected by ionizing radiation, the functional and structural changes that ensue are variable, depending not only on radiation characteristics, such as dosage and ion density, but on characteristics of the particular reacting biologic system as well. Such facts need to be considered in countermeasures based on the proposed concept of cancer . It is suggested that effective countermeasures will take into account, among other things, the evidence regarding high-level oxy genation, indications of the affinity of oxygen and negative ions; reported benefits of reduction of tissue oxygen requirements ; and the potential of lactic acid inhibition . Further research will test the validity of these specific points and of the oxygen-stress-reaction theory as a whole . References and Notes R. POCHE, O. MITTMANN and O. KNELLER, Z . Krebsforschung 66, 87 (1964) . 2.
M. POLLARD, Paper presented at the 1963 meeting of the Federation of American Societies for Experimental Biology .
3.
O. WARBURG, Science 123, 309 (1956) .
4.
In very recent months so many papers have been presented on this subject that it seems expedient for present purposes to refer to 1963 and 1964
Vol . 3, No. 8
ON A UNIFYING CONCEPT OF CANCER
927
issues of Medical Tribune . For example, in the March 2, 1964 issue there is a report on a special conference sponsored by the New York Academy of Sciences and the National Academy of Sciences; the December 6, 1963 issue reviews a paper by O. WILDERMUTH presented at the annual meeting of the Radiological Society of America . The March 2, 1964 issue also contains a report of research by J. W. BEAN relating to individual differences in susceptibility to oxygen toxicity under hybaroxic conditions . 5.
J . T . MALLAMS, paper presented at a special conference on oral cancer, held in 1983 under the auspices of the American Society of Oral Surgeons; also R. J. JOHNSON, paper presented at the 1963 meeting of the Canadian Association of Radiologists .
6.
H. LABORIT et al., Int . Rec. Med. & Gen Prac. Clinics 167, 309 (1954) .
7.
"Hemorrhagic shock: metabolic effects", Science 141, 536 (1963) .
8.
B. FERBER et al., Cancer in New York State, Exclusive of New York City, 1941-1960 .
Bureau of Cancer Control, New York State Department of
Health, Albany (1962) . 9. 10.
J. MEAD, Cancer J. for Clinicians il, 92 (1961) . H. L. LOMBARD, in The Physiopathology of Cancer (Edited by F. HOMBURGER) p . 985 . Hoeber-Harper, New York (1959) .
11 .
G. G. DUNCAN, Diseases of Metabolism. Saunders, Philadelphia (1959) .
12 .
H. KRUGER, paper presented at the 1964 meeting of the Latin American Society of Pathology .
13.
R. J. HUEBNER, paper presented at the 1963 meeting of the National Academy of Sciences during an Academy symposium of virus-cancer relations.
14.
J . E . GRIFFIN and I. H. KORNBLUEH, Int . J. Biometeor . 6, 29 (1962) .
15 . - S. W. TROMP, Psychical Physics . Elsevier, Amsterdam (1949) . 16 .
L. L. VASILEV, Amer . J . Phys . Med. 39, 124 (1960)
17.
A. P. KRUEGER and R. F. SMITH, Roy . Soc . Health J. _79, 642 (1959) .
18 . 20 .
J. B. DAMS, Aerospace Medicine 34, 35 (1963) . A. H. FREY, Inst. Radio Engrs . Trans. Bio-med. Electron . 8, 12 (1961) . K. H. KINGDON, Nature, Lond. 189, 180 (1961) .
21.
E . P. RADFORD, Jr. and V. R. HUNT, Science _143, 247 (1964) .
22.
H. J. CURTLS, Science 141, 686 (1963) .
19 .
928 2S .
ON A iJNIFYING CONCEPT OF CANCER
Vol . 3, No. 8
H. SELYE, The Stress of Life . McGraw-Hill, New York (1956) . In a recent communication to the author, Dr. Selye refers to his work on the induction of sarcomas by "Tissue Scaffoldings", which presumably produce only mechanical stress, and suggests that this may give further support to a unifying concept in which cancer is considered to involve characterisric processes but no single distinctive cause .
REVIEW ON A UNIFYING CONCEPT OF CANCER Leon Brody Director of Research, Center for Safety Education, New York University Washington Square, New York 3, N. Y. (Received 19 June 1964) An oxygen-stress-reaction theory is outlined as an umbrella for divergent views and isolated facts . IN cancer the spectrum of causation appears to be remarkably broad. There is a constant flow of studies purporting to relate the incidence of cancer to a great variety of factors, usually physical, chemical, or viral . As a result assertions have been made that cancer may actually involve a "family" or scores of diseases . The vexing situation is also reflected in the NationalCancer Institute's screening of tens of thousands of chemical compounds in the search for cures and controls . Not only are there divergent views as to types of cancer from a casual standpoint, but even with respect to a relatively definable type conflicting reports appear . Thus the recent issuance of the U. S. Public Health Survey link ing cigarette smoking and lung cancer, has been followed by a medical reportl that there is no statistical connection ; that air pollution by gasoline vehicles and industrial gases is a more likely cause of lung cancer . As a matter of fact, previous experimental studies have shown that the concentration of pollutants in ambient air may be sufficient to produce malignant transformations . Simi1 laxly, proponents of viral causation are confronted with reported evidence that cancers may readily be produced in rats and mice raised under presumably virus-f ree conditions. It seems obvious that a unifying concept of cancer would help to reduce confusion and accelerate progress . Such a concept is possible if common denominators can be located among various carcinogenetic processes or even deduced from düferent therapeutic measures that appear to have contributed in some degree to cancer management . One is encouraged at least to conjec917
91 8
ON A UNIFYII~TG CONCEPT OF CANCER
Vol . 3, No. 8
tore along these lines . Warburgs Theory and Some Implications There is reason to believe that a sound basis for a unifying concept is to be found in Otto Warburgs studies of cell metabolism, which now extend over a period of more than three decades . A cell needs oxygen to produce energy for survival and development ; in a sense it breathes . In this respect Warburg3 observed a dramatic difference between a cancer cell and a normal cell. Whereas a normal cell obtains most of its energy through respiration, a cancer cell depends largely on fermentation for its source of energy . It was presumed therefore, that cancer is initiated when the mechanism by which individual cells use oxygen (or breathe) is damaged. The cell-injuring agents range from radia.tfon to chemical compounds. For a period of time the cells continue to struggle with damaged respiratory mechanisms . Finally, to overcome their oxygen shortage, they resort to a new form of energy production -- fermentation . With fermentation oxygen is not necessary . However, fermentation is not as efficient as respiration . Under the former there is incomplete combustion of sugar, with lactic acid as the end product ; and cell components that normally would be used for growth and reproduction are utilized for energy production. While normal cells, which provide complete combustion of sugar (with carbon dioxide and water as end products), differentiate or organize themselves into normal tissue or organs, fermenting cells grow wild and form masses that may take possession of vital tissues and organs In view of this theory, what are known as "sleeping cancer cells" may well be cells that have been damaged but have not yet made the transition to fermentation, perhaps because the extent of injury is borderline (additiona.l stress may bring it to the critical point) or because the resistive or adaptive capacity of the cells is at a relatively high level. Cancer control, then, would need to take into account objectives of these kinds: (1) to maintain normal cell respiration ; (2) to prevent fermentation that has nothing to do with normal function (Warburg, in view of his findings con cerning the end product of fermentation, has suggested that inhibition of the enzyme forming lactic acid should prevent cancer cells from developing ; (3)
to restore the respiration process as soon as possible after injury of the cell . The latter, of course, assumes a reversibility of effects .
Vol . 3, No . 8
ON A UNIFYII~TG CONCEPT OF CANCER
91 9
In any case the common denominator or critical phenomenon in carcinogenesis may be hypothesized to reside in oxygen supply and utilization at the cellular level . Numerous tests of this hypothesis are possible .
The following
are illustrative : 1.
That high-pressure or high-level oxygenation is helpful in cancer control;
2.
That reduction of the oxygen requirements of tissues, within limits, tends to counteract stress reactions that interfere with normal metabolic functions;
3.
That there is a high incidence of cancer among aerobic organs and a low incidence in organs where oxygen is used efficiently ;
4.
That there is a greater incidence of cancer in the diabetic population, because hypoxia aggravates the metabolic difficulties associated with diabetes ;
5.
That malignant tumors may be frequent at high altitudes, where oxygen supply is reduced to functionally hypoxic levels .
Evidence or observations relating to these tests of the hypothesis may be categorized as follows . Hybaroxic Radiation Dramatic results are being reported for hyperbaric oxygen therapy in many conditions, ranging from arterial insufficiency to carbon monoxide poisoning and carcinoma . 4 It has been known for years that the effects of radiation are enhanced by increasing oxygen in the tissues at the time of irradiation; or conversely, that a cell deprived of oxygen is less sensitive to X-rays .
With
accumulating evidence that many or most of the cells in malignant tumors are anoxic or hypoxic, one has a logical base for explaining the greater success of cancer radiotherapy under hyperbaric oxygenation .
Oxygen breathed under two
or three atmospheres of pressure tends to saturate the blood and thus provide a higher level of oxygen even in the center of tumors, facilitating their destruction by irradiation.
In some individuals such procedure may entail oxygen
toxicity, possibly because C02 levels and tissue acidity are elevated, but various drugs are reported to be proving effective, experimentally, in affording protec tive action.
In any case the over-all evidence tends to affirm the first test of
the hypothesis of this paper .
920
ON A UNIFYII~TG CONCEPT OF CANCER
Vol . 3, No. 8
Regional Infusion with Hydrogen Peroxide This procedure is intimately related in concept, application, and effect to hybaroxic radiation, for the indications are that hydrogen peroxide irüusions
increase oxygenation within tumors and enhance tumor response to irradiation . 5 The beneficial activity of peroxides in attacking tumor cells was suggested by Warburg long ago .
Now, by regional perfusion, it is being found that high con-
centrations can be attained where particularly needed.
ù~jection into the blood
supply of the tumor makes for greater selectivity in destroying cancer cells by irradiation, with minimal damage to surrounding tissue. another technique is noteworthy : iontophoresis .
In this connection
The process of ionizing drugs
with an electric current so that they penetrate tissue is not new .
As a matter
of fact such experimentation with hydrogen peroxide was applied to tumors of rats thirty-five years ago at the Cancer Institute of the University of Berlin . This procedure is mentioned now because of its possible implications with regard to the discussion of ions later in this paper .
In any case, reported re-
sults with regional infusion of hydrogen peroxide again tend to support the first test of the stated hypothesis . Hypothermia, Hy~ometabolism, and Shock Surgeons have long been aware of advantages to be gained by lowering body temperatures during operations in which the circulation must be interrupted . The effect of hypothermia is to reduce oxygen requirements and consumption in the tissues, thereby lowering metabolism and cellular oxidation. for the subject of this paper immediately suggests itself ;
An implication
indeed, it is not too
surprising to note that more than one hundred years ago a method of body refrigeration was employed in an attempt to treat carcinoma . In recent times Laborit and othersg, combining hypothermia and drug complexes, have concerned themselves with artificially induced hibernation in man, somewhat similar to the condition of hibernating mammals and cold blooded animals .
Their objective: to calm disorganized reactions of the neuro-
endocrine system by effecting temporary aba~xionment a~f metabolic processes that tend to run counter to normal life function . Not only has such procedure proved valuable in surgery, it has also demonstrated effectiveness as an adjunct in protecting against consequences of trauma or shock and in treatment of cerebral hypoxia . As indicated by Laborit's work and elsewhere, hypometabolism may be
Vol . 3, No. 8
ON A UNIFYING CONCEPT OF CANCER
induced or potentiated by a number of drugs . has such an influence on nervous tissue .
921
Chlorpromazine, for example,
La.borit found the barbiturates par-
ticularly effective in connection with artificial hibernation because of their effect on cellular metabolism, in decreasing oxygen requirements .
The possible
significance of the latter fact is illustrated by evidence of enhanced tissue tolerance of high CO saturation of the blood . Thus, the second teat of the hypothesis of this paper seems to be further affirmed .
Of course, there is need for additional exploration of the relevance
of these concepts and procedures to the phenomena of cancer .
It is interesting
to note, however, that so-called "irreversible shock" (or stress) is considered to produce decreased tissue perfusion and utilization of oxygen and, at least in the case of hemorrhagic shock, causes a marked elevation in the blood concentrations of glucose and lactic acid, among other effects .
Significantly, these
alterations are characteristic of hypoxia and indeed appear to correspond with phenomena of cancer as previously set forth.
The question is inevitable : Is
there a parallel between stress reaction and cancer? More boldly, do they entail the the same dynamics, from initiation to outcome? ü so, within what limits, considering individual differences and tolerances, can hypometabolic measures be employed for purposes of prevention, control, and reversal? Miscellaneous Clinical and Statistical Considerations The three additional tests of this paper's hyposthesis relate to the following: (1) The incidence of cancer in aerobic organs and in organs where oxy gen is used efficiently . There is a dearth of dependable statistics in this area. However, data compiled by the New York State Bureau of Cancer Control for the period 195819ô0 8 indicate a particularly high incidence for the kidney, brain (and central nervous system), and liver (primary) . The kidney is an especially aerobic organ and therefore very susceptible to hypoxia . The subnormal levels of cerebral oxygen consumption in conditions ranging from senile psychosis to alcoholic coma are evidence of the brain's susceptibility to hypoxia . The significance of liver incidence of cancer probably derives from the fact that alcohol impairs the ability of tissues to utilize oxygen supplied by the blood stream . On the other hand, tumors of the heart are a medical rarity. 9 Although the heart gets only one tenth of the oxygen received by the entire body, no organ uses oxygen more
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efficiently . Such data tend to affirm the third test of this paper's hypothesis . (2) ire incidence of cancer in the diabetic population. On the assumption that diabetics are subject to or exposed to hypoxiainducing conditions roughly to the degree applying to the general population, but because of the metabolic difficulties intrinsically associated with a condition where sugar is inadequately absorbed or utilized by body cells, it was subhypothesized that there would be a relatively high incidence of cancer among diabetics. Available facts seem to bear this out. Early datal0 show very substantial, positive correlations . This is supported by a more recent appraisalll attesting to the greater incidence of cancer in the diabetic population and observing that the relationship is becoming increasingly apparent as more diabetics live longer into the "cancer age" . It is noteworthy that in the majority of cases the onset of malignant disease reportedly occurs after the diabetes has been established . (3) The incidence of cancer at high altitudes . It has been believed that malignant tumors are not frequent in communities located at high altitudes . Presumably one of the principal reasons for this belief is the reduction in man-made air pollutants with increasing elevation . Al though there is some validity in the latter fact, it relates to a limitied casual concept, for another concomitant of high altitude is reduced oxygen supply . While natives and others tend to adjust to such hypoxic conditions, the fact remains that it is an adjustment to conditions that are more or less incompatible with inherent biological processes . Perhaps this reason helps to account for recent findings, 12 through autopsy and biopsy, that carcinoma of the cervix, skin melanomas, and gastric carcinomas occur frequently among residents of high-altitude communities . The Question of Viral Causation Numerous viruses are known to cause cancer in animals ; many scientists believe that viruses cause at least some human cancers ; no virus has yet been proved to cause human cancer . In the quest for a unifying concept there may be some significance in the mechanism of viral action. It is commonly thought that a virus will puncture a cell wall, injure the cytoplasm of the invaded cell, and disrupt nuclear function so that the cell turns from its normal activity to the production of new virus particles in the image of the invader (which then burst out to infect other cells) . In other words, because a virus is unable to reproduce by itself, it multiplies by using material and energy from ordinary human
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cells . Again the hypothesized common denominator in cancer causation suggests itself : disturbance or destruction of the cellular processes of respiration and oxygen utilization. There may be supporting implications in relatively recent reportsl3 that viruses of a kind known to cause common respiratory illnesses in man, from colds to whooping cough and pneumonia, are also capable of causing cancer in animals . One is tempted to wonder whether such illnesses may represent incomplete, reversible "cancers" of the respiratory tract. More objectively, it is suggested that correlational studies of "cold proneness" and cancer incidence of related varieties would not be unwarranted . The Possible Role of Ionized Air Reference has previously been made to the fact that biologic systems are sensitized by oxygen to the effects of ionizing radiation and that this has some relevance to the reported usefulness of hybaroxic radiation therapy in the management of cancer . Air ions, which are produced by both man-made and natural radiation, may indeed have a broad role in the various phenomena of cancer, contributing to a unifying concept derivable from Warburgs theory and extended in the concluding section of this paper . Of primary significance is the indication that positive ions represent carbon dioxide molecules which have lost electrons, while negative ions represent oxygen molecules to which extra electrons have become attached as a result of a highly binding electron affinity . l4 Admittedly, there is much more speculation than evidence regarding the various effects of ionized air and the conditions under which they obtain. Within these limits certain interrelationships of fact and .opinion are suggested:l 5-19 (1) Tons entering the respiratory tract are repulsed or attracted, depending on the electric charge of the membranes . The
charge of the membranes of .alveolar cells is usually positive, enabling them to adsorb mainly negative ionic charges . This
tends to facilitate normal function. On the other hand, strongly concentrated,positively charged air has some of the same biological effects as shortage of oxygen and excess C02 in the blood . (2) Negative ions carried by the blood to body cells, according to Vasilyev, serve to restore the normal negative
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charges of those cells - charges that are reduced by aging and disease - and tend to maintain normal metabolic processes. The mechanism of such action is said to be through an effect on the permeability of cell membranes and through desirable reaction with certain enzymes . (The latter, reportedly, may be deactivated or poisoned by positive ions. ) (3) It has also been indicated that negative ions stimulate the secretion of anti-inflammatory gluco-corticoids, while positive ions either inhibit this secretion or stimulate the secretion of inflammatory corticoids; and that under exposure to positively ionized air there is evidence of enhanced vulnerability of tissue to trauma, the converse applying in the case of negatively ionized air . With the reported affinity of oxygen and negative ion charges, there appears to be some rationale - within the scope of this paper's hypothesis for observations that negative air-ion therapy inhibits the development of
tumors in rats and mice. Such therapy, however, is impeded by the fact that under normal atmospheric conditions, high ion concentrations are difficult to achieve because of ion mobility and short life. On the other hand, this same fact may account at least in part for the relative effectiveness of hybaroxic procedures . With the currently high interest in the relationship between cigarette smoking and cancer, it is noteworthy that a charged-particle or ion hypothesis has been advanced20 as an alternative to the carcinogenic chemical concept (involving, for example, possible effects of tobacco tars) . There now is reason to believe that either approach is too limited. Thus one may point to the reported synergistic action of ionizing radiation and cigarette-smoke extracts, or other chemical agents, in experimental cancer production. 21
Finally, in view of the indications that negative ions enhance and positive
ions inhibit oxygen utilization, there appears to be justüication for expanded research on electrical properties of tumor cell surfaces (as compared to nor
mal cell surfaces) and on methods of alt Bring surface charges so as to attract negative ions and repel positive ions. The Involvement of DNA There has been increasing attention to the role of the deoxyribonucleic
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acids (DNA) that constitute the chromosomes of the cell, residing in the cell nucleus . 22 It is indicated that carcinogenic-related DNA changes occur when cells are damaged to the extent that certain of the normally vital cellular functions are impaired or eventually destroyed . Indeed there is a tendency to consider DNA changes as basic to the entire problem . But in the light of previously presented fact and theory, it is here proposed that DNA changes are better viewed as one of the critical characteristics or concomitants of the over-all carcinogenic process rather than as the primary definitive or causal aspect . Of course, when cell division is required, then the role of DNA assumes greater significance . But it is noteworthy that some DNA molecules apparently are not put to use in ordinary function and therefore may constitute some kind of reserve ; further, that there are mutations which may change a DNA molecule in such a way that the cell functions somewhat differently but does not die . Toward a Unifying Concept :
Recapitulation and Extension
It has been suggested in this paper that the common denominator or critical phenomenon in carcinogenesis resides in inadequacy of oxygen supply and utilization at the cellular level. This concept, crudely supported by facts and theory relating to specified sub-hypotheses and various prominent views on cancer, seemingly is applicable to an understanding of reported causation by numerous physical, chemical, and viral agents . These may all be considered in relation to stress and stress reaction involving cellular oxygen supply and utilization . ü so, the essential dynamics of carcinoma are reduced to relatively definable proportions . Selye's stress theory23 holds that many diseases have no single cause or specüic pathogen but are due largely to non-specific stress and pathogenic situations resulting from inappropriate responses to such non-specific stress . In other words, the stress phenomenon has its own characteristic form but no distinctively specific cause. This parallels the interpretation of cancer in the present paper . Further, Selye has emphasized that one of the principal "lessons" learned from thirty years of research on stress is that the body can meet very diverse aggressions (from irradiation to nervous tension) with the same adap tive defense mechanism .
His "general adaptation syndrome" specifies three
stages of response : (1) the "alarm reaction", when body systems are activated to counter the stress ; (2) resistance and adaptation, when a balance between
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stress and the host reaction is obtained ; (3) exhaustion, when defense processes break down and degeneration sets in. Again there is a parallel to the proposed concept of cancer, particularly as it reflects Warburgs theory. Damage to cellular machinery for utilization of oxygen (or interference with normal machinery function) tends to be followed by a struggle for survival and then, in many or most cases, by fermentation and normal cell destruction . The second stage seems to provide some rationale for observed delays in cancer development or what has been referred to as "sleeping cancer cells". Of course, most mammalian organisms seem to be constructed in such a way that they can deal with most everyday stress situations and emerge unharmed, or at least without irreparable damage to organs or tissues . Built-in regulatory and adaptive mechanisms apparently make possible a dynamic type of equilibrium or what may be termed "variable homeostasis", for a given individual . But individual differences in potential or actual tolerance do exist. For example, while all biologic systems are affected by ionizing radiation, the functional and structural changes that ensue are variable, depending not only on radiation characteristics, such as dosage and ion density, but on characteristics of the particular reacting biologic system as well. Such facts need to be considered in countermeasures based on the proposed concept of cancer . It is suggested that effective countermeasures will take into account, among other things, the evidence regarding high-level oxy genation, indications of the affinity of oxygen and negative ions; reported benefits of reduction of tissue oxygen requirements ; and the potential of lactic acid inhibition . Further research will test the validity of these specific points and of the oxygen-stress-reaction theory as a whole . References and Notes R. POCHE, O. MITTMANN and O. KNELLER, Z . Krebsforschung 66, 87 (1964) . 2.
M. POLLARD, Paper presented at the 1963 meeting of the Federation of American Societies for Experimental Biology .
3.
O. WARBURG, Science 123, 309 (1956) .
4.
In very recent months so many papers have been presented on this subject that it seems expedient for present purposes to refer to 1963 and 1964
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issues of Medical Tribune . For example, in the March 2, 1964 issue there is a report on a special conference sponsored by the New York Academy of Sciences and the National Academy of Sciences; the December 6, 1963 issue reviews a paper by O. WILDERMUTH presented at the annual meeting of the Radiological Society of America . The March 2, 1964 issue also contains a report of research by J. W. BEAN relating to individual differences in susceptibility to oxygen toxicity under hybaroxic conditions . 5.
J . T . MALLAMS, paper presented at a special conference on oral cancer, held in 1983 under the auspices of the American Society of Oral Surgeons; also R. J. JOHNSON, paper presented at the 1963 meeting of the Canadian Association of Radiologists .
6.
H. LABORIT et al., Int . Rec. Med. & Gen Prac. Clinics 167, 309 (1954) .
7.
"Hemorrhagic shock: metabolic effects", Science 141, 536 (1963) .
8.
B. FERBER et al., Cancer in New York State, Exclusive of New York City, 1941-1960 .
Bureau of Cancer Control, New York State Department of
Health, Albany (1962) . 9. 10.
J. MEAD, Cancer J. for Clinicians il, 92 (1961) . H. L. LOMBARD, in The Physiopathology of Cancer (Edited by F. HOMBURGER) p . 985 . Hoeber-Harper, New York (1959) .
11 .
G. G. DUNCAN, Diseases of Metabolism. Saunders, Philadelphia (1959) .
12 .
H. KRUGER, paper presented at the 1964 meeting of the Latin American Society of Pathology .
13.
R. J. HUEBNER, paper presented at the 1963 meeting of the National Academy of Sciences during an Academy symposium of virus-cancer relations.
14.
J . E . GRIFFIN and I. H. KORNBLUEH, Int . J. Biometeor . 6, 29 (1962) .
15 . - S. W. TROMP, Psychical Physics . Elsevier, Amsterdam (1949) . 16 .
L. L. VASILEV, Amer . J . Phys . Med. 39, 124 (1960)
17.
A. P. KRUEGER and R. F. SMITH, Roy . Soc . Health J. _79, 642 (1959) .
18 . 20 .
J. B. DAMS, Aerospace Medicine 34, 35 (1963) . A. H. FREY, Inst. Radio Engrs . Trans. Bio-med. Electron . 8, 12 (1961) . K. H. KINGDON, Nature, Lond. 189, 180 (1961) .
21.
E . P. RADFORD, Jr. and V. R. HUNT, Science _143, 247 (1964) .
22.
H. J. CURTLS, Science 141, 686 (1963) .
19 .
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H. SELYE, The Stress of Life . McGraw-Hill, New York (1956) . In a recent communication to the author, Dr. Selye refers to his work on the induction of sarcomas by "Tissue Scaffoldings", which presumably produce only mechanical stress, and suggests that this may give further support to a unifying concept in which cancer is considered to involve characterisric processes but no single distinctive cause .