Cellular Cancer Therapy, part 2
The neoplastic cell has many characteristic biochemical aspects. One of them, biochemical convergence, is very important for this study. The cells that make up each normal tissue have characteristic enzymatic equipment and therefore, characteristic enzymatic activity as well. For example, some enzymes are very active in kidney tissue, but not very active at all in the liver, and vice versa. The neoplastic cell, on the other hand, has patterns that are less characteristic than those of the normal tissue from which they originate. A renal neoplasia with very malignant cells can be, according to its pattern of enzymatic activity, much more similar to a hepatocellular carcinoma than to the cells of a normal kidney. There is, then, a tendency of the diverse patterns of enzymatic activity to converge towards a common pattern in malignant neoplasias. This is nothing more than the simple equivalence with the morphological changes called anaplasia, which usually prevent the recognition of the site of origin of a neoplasia by its histological characteristics. The characteristic features of a tissue are those that individualize it morphologically as well as biochemically. In neoplasias, which are not very differentiated, these features are greatly reduced.
With respect to biochemical convergence, the cell’s energy metabolism has been investigated very much since the papers of Warburg and his collaborators in the 20s. Warburg observed that the malignant cell produces large quantities of lactic acid from glucose and that this property is not notably reduced in the presence of oxygen. That is to say that the malignant cell shows an abnormally infrequent Pasteur effect. Therefore it was believed that this high glucolysis rate in aerobiosis and anaerobiosis characterized malignant disturbances. In malignant tumors elevated anaerobic metabolism can be observed. On the other hand, normal tissue, with the exception of embryonic, placental, retinal and neurocortical tissues show anaerobic glucolysis at only 10—20% of that of the more malignant neoplasias. In malignant neoplastic tissue, glucolysis is reduced up to 50% in the presence of oxygen, while in normal tissues anaerobic glucolysis is practically reduced to zero in the presence of oxygen.
The malignancy of a tumor can be correlated, according to Warburg and his disciples, to an increase in the fermentation processes and to a decrease in respiration. They also state that a deficiency in respiration is what is the basic cause of increased fermentation. Other investigators think that anaerobic glucolysis of malignant neoplasias is so high that normal respiration and Pasteur effects cannot reduce the glucolysis to. the low normal levels. In spite of the intense investigation on the part of researchers, the energy metabolism of malignant neoplasias continues to be a very controversial field, especially in two aspects: the role of the defects of the respiratory system in the production of the high glucolytic activity of the poorly differentiated neoplasias, and the fundamental importance of these metabolic abnormalities as causes of the malignant neoplasia.
Plotter (1968) described a third characteristic of neoplasias. For his experiments he used hepatomas or carcinomas of rat liver cells and discovered that each neoplasm showed a pattern of enzymatic activity different from that of the normal liver and characteristic of the individual lesion. The interesting part of this discovery is that the activity of any individual enzyme was much more constant in the neoplasia than in the normal liver, given circadian cycles and environmental stimuli of different kinds. The normal liver could adapt its enzymatic activities to cope with the circumstances; on the other hand, neoplasias were less adaptable. The different activities of different enzymes in various neoplasms were within the limits that could be produced in the normal liver, but the activities of the normal liver could be varied more easily. In 1968, Pitot presented data indicating that the different levels of enzymatic activity can be conditioned not by variations in the specific messenger RNAs, but by alterations in its stability or in the efficiency of the translation of the individual message into protein. It seems that a crucial step in the synthesis of enzymes, possibly that of translation, tends to lose its normal regulating capacity in neoplasias.
Though once formed neoplasias tend to lose their specialized differential characteristics in terms of enzymatic activity, they show themselves to be less flexible, less adaptable and perhaps more specialized than the normal cells in which they originated.
It has already been said that malignant neoplasias undergo the loss of special products or functions. For example, an epidermic neoplasia can produce little or no keratin and an abdomyosarcoma (esp. "rabdomiosarcoma"?) can synthesize only scarce amounts of myosin. However, many neoplasms can produce substances typical of other organs, completely different tissues, for example: some broncogenous carcinomas produce insulin. The heterologous elaboration of hormones has been described by Lebovitz (1965) in very different neoplasms. Specific cell antigens can also be inappropriate (Olenov and Fel, 1968). The cells of tumors are deficient, in a characteristic way, in terms of these normal antigens; but frequently a substitution for other antigens apparently occurs. A renal neoplasia, for example, can show characteristic hepatic antigens. Besides showing the antigens specific to other organs, tumoral cells produce antigens that are not found in [illegible line in manuscript — p. 19] Supposedly each cell of the body contains all the genetic information carried in the egg, but in malignant disturbances some of this information, normally inactive, is used in a capricious and unpredictable way.
A neoplasia can appear in organs or tissues that are undergoing physiological hyperplasia. The premature neoplasia, which originates in such locations, is frequently made up of very benign cells that differ only slightly from normal cells. Like normal cells, they need, though to a lesser extent, continuous exogenous stimulation to maintain hyperplasia. In many premature neoplasias that have not developed very much, hereditary modification is not enough to maintain the hyperplasic state when the stimulus for common physiological hyperplasia is lacking. These lesions, though neoplastic, depend on external stimuli. A good example of this is found in some mammary carcinomas. Normal mammarian epithelium shows rhythmic physiological hyperplasia during the menstrual cycle. Estrogens are particularly efficient as hormonal stimuli. Therefore, it comes as no surprise that many mammary carcinomas, especially those that are relatively premature, depend on estrogens for their development. They regress if these hormones are no longer available because of ovarectomy, making this a palliative because, we reiterate, cancer is a general alteration and simply removing the ovaries will not compensate for the other physical and chemical alterations that are present in a cancerous patient’s whole organism. Aggravating this is the fact that by depriving the organism of this source of specific chemical elements, its chemical imbalance will worsen with time, but carcinomas, if they continue to progress, no longer depend on estrogen. In a similar way, ovarian neoplasias can depend on gonadotropins, thyroid neoplasias on thyrotropin, etc.
Though the word dependence is ordinarily applicable in the case of hormonal dependence, undoubtedly other, not so easily recognizable, kinds may exist in different premature neoplasias.
A dependence, though rather different, of some neoplasias is particularly interesting because of its possible therapeutic importance. Normal cells, in general require little or no exogenous asparagin. On the other hand, some neoplastic cells cannot grow without an exogenous supply of it. These neoplasias can be treated by administering asparaginase. This enzyme can effectively deprive the cell of asparagin without causing lesions in most of the normal cells, but it still has to be seen exactly how many human neoplasias depend on asparagin and during what period (Boyse et al, 1967).
As for the reactions of the host cell, one can say that the growth of almost all neoplasias depends on adequate stroma of connective tissues and adequate blood supply. Connective tissues are normally tissues of the host that proliferate because of neoplasia. Most neoplasias cannot grow more quickly than the vascular system that irrigates them and many malignant tumors show extensive necrosis because they overstep the limits of their blood supply or because the mechanical pressure of the tumor mass stops or decreases the blood flow. The factors that produce neoplastic stroma and blood supply are unknown but a chemical agent called the angiogenesis factor has recently been isolated from tumor tissue, and which, according to Gimbrone et al., 1972, makes capillaries proliferate spectacularly.
In malignant tumors the vascular system is frequently abnormal, for instead of being irrigated by a typical layer of capillaries, sometimes they have a system of large, thin-walled sacs. The blood stream is typically slow and gas interchange is insufficient. Perhaps this is why neoplasias show elevated anaerobic glucolysis and why the intracellular pH is abnormally low. These vascular sacs are quite fragile and the phyoxia caused by temporal blood hypotension can cause extensive hemorrhage within the tumor.
In spite of the fact that most malignant neoplasias have a vascular blood network, the stroma thus created often does not have nerves and lymphatic vessels, though there are variations from one tumor to another and some do have nerves, lymphatic vessels or both.
Some malignant diseases, especially schirrhous carcinomas of human mammary glands induce an intense desmoplastic reaction, for fibrous tissues can make up a much greater portion of the tumoral mass than the neoplastic cells.
One characteristic abnormality of inflammation is possibly related to the qualitative abnormalities of the distribution of blood vessels, because in many tumors in experimental animals it has been observed that certain stimuli, such as foreign bodies introduced in neoplasias, do not produce inflammation (Mahoney and Leighton, 1962). This very interesting abnormality can make an important contribution to the propensity of some tumors to become infected with bacteria and in this manner permanently tolerate them.
Cachexia is the most important physiological effect of malignant tumors. In man, one of the most prominent symptoms of cancer is the loss of weight. However, though the energetic necessities of an animal with a malignant tumor are greater than those of normal animals, and at the same time their ingestion of food is usually diminished, these facts do not explain fully cachexia. In malignant neoplasm, the elevated consumption of nitrogen in the diet seems to be useful for annulling the effects of neoplasia which can be considered, from a biological point of view as a parasite that attracts amino acids from the general metabolism to use them for its own benefit.
Many malignant neoplasms produce an intense effect on the host independently of purely mechanical effects. One effect that is basically constant in animals is the depression of the activity of the catalase in the liver. This, in general, does not happen in cancer in man, possibly because human neoplasias rarely reach the proportional sizes they do in rodents. Anemia is a frequent manifestation of neoplasias even when the tumor does not attack the bone marrow. To’ explain these effects, some investigators have reported toxic substances liberated by neoplastic tumors and have called them, as a group, toxohormones (Nakahara, 1960).
As for the characteristics of the surface of neo— plastic cells, they are different enough from any normal cell to be treated as foreign by the host’s immunological mechanisms. Consequently, the immunity of the host is of fundamental importance for the biology of neoplasia. Only up to a few years ago has the opinion been sustained that immunity against the neoplasm is theoretically impossible, that is to say, it is not possible that the neoplastic cell, as a component of the "same" organism, be the target of an immune reaction. Nowadays it is thought, possibly mistakenly, that almost all incipient neoplasias can be eliminated by an immune reaction before they reach a large size. Clinical tumors, like those that a doctor can diagnose, would be the small number of other neoplasias that for some reason escape this defense mechanism. In the treatment of cancer, it is not sufficient to use immunotherapy.
The treatment of cancer requires the use of immunotherapy as well as the application of different chemical compounds, as is done in the course of Donatian Therapy.
Two kinds of evidence support the importance of the immunological mechanisms: the first is that animals can be immunized by antigens of the tumoral tissue, in such a way that the development of transplanted tumors is notably inhibited and suppressed; and the second is that immunological reactivity and the incidence of neoplasias are correlated in modified conditions.
Given that the fundamental molecular basis of the cancerous cell is still unknown, the details of the cause should be reduced to simple descriptions of environmental and genetic factors, as well as speculations about how they act. The search for the cause has found a plethora of etiological factors. In general an additive effect of very different factors is found in the production of neoplastic tissues, in such a manner that it would be out of place to talk about the cause of cancer because it is a multifactorial sickness.
Now we will describe some specific causal agents, though it should be kept in mind that none of the agents we will describe can be considered to be the cause of any neoplasia; they all are.
We have two disturbances in mind: Burkitt’s lymphoma and carcinoma of the cervix. The first is a sickness of childhood that occurs in Central Africa. The geographical distribution of this disease has led to the belief that its transmission is probably due to an insect carrier. This virus can develop because it finds the appropriate terrain; without this biochemical terrain, it simply does not develop at all. Immunological studies have indicated a common antigen in almost all cases, which is capable of producing an antibody response. Herpes group viruses have been indicated as the causal agents of both Burkitt’s lymphoma and infectious mononucleosis (Heule et al, 1968). This is a febrile, contagious and frequently self—limiting disturbance which is found among young adults. In our opinion it can be attributed to alimentation, climate and the digestive process.
It has long been thought that a cervical carcinoma can be correlated with coitus and, in particular, with men who have not been circumcised. In this way, the incidence of the ailment is low among nuns and Jewish women. It has only recently been shown through epidemiological studies that it is not coitus itself that is correlated with the incidence, but the number of different partners with which it is carried out, for the larger the number of partners, the greater the probability of appearance of a cervical carcinoma. This fact points strongly to the extent to which this ailment is venereal in nature and probably transmitted by some men who are not circumcised. Once again, a Herpes group virus (not of the same type as those causing canker—sores) has been isolated in an elevated percentage of the cases. Unfortunately, since the advent of antibiotics it has been thought that venereal diseases can be controlled and even cured. More concretely, gonorrhea certainly has been cured, though in very few cases, but the great majority of cases are not cured. What happens is that certain chemical elements of the gonococcal secretions change without annihilating it. These chemical elements do not lodge in the gonococcus and react as if it had died. The patient is subsequently released as cured after the application of however many million units of penicillin and other antibiotics. In fact the gonococci, one could say, become "spores" and continue to generate their toxins which, if they find the appropriate terrain, will produce cancer of the prostate or of the cervix. This is why the sexual liberation has increased venereal infection, since it was believed that this is no longer a danger, because of the existence of antibiotics. Though laboratory exams indicate that the gonococci are no longer present, they still are and will continue to cause damage; this is even more dangerous because the doctor has led those patients to believe they are cured, and believing this they unwittingly proceed to spread these venereal diseases, which now are masked by the appearance of other germs, though the principal hidden one is still the gonococcus. It is possible add one or more viral agents to this scenario, but they would still not be the causal factor. All of them, indeed, have to find the appropriate cancerogenic terrain for the cancer to be able to evolve. What happens in experimental animals is very different from what happens in humans since their chemical and physical make up is very different.
It is a mistake to try to find a virus as the cause for cancer; the causes are many and of a physical and chemical nature. In any case, it is said to be virtually certain that many neoplasias are of viral origin, as has been demonstrated in animals In spite of our objections, this is still believed by many.
The two major classes of oncogenic viruses known are RITA and DNA viruses. In the chart below we offer the names of some of the better—known examples of each, though many more are still to be discovered.
Percival Pott observed almost 200 years ago that chimney—sweeps were very particularly apt to get cancer of the scrotum. Since then hundreds of oncogenic chemical agents of different kinds have been identified, but almost all of them in the last 50 years. Though it was obvious that the oncogenic virus should be found in soot, in the case of chimney sweeps, this agent was not isolated nor identified in approximately 150 years of research because, in spite of the many attempts, neoplastic tumors could not be induced with soot or tar in laboratory animals. Only in 1915, when Yamagiwa and Ichikawa patiently painted tar on rabbits’ ears every two or three days for a year, were some experimental cancers finally produced in this manner. Once a biological method was available, it was possible to fractionate the raw material and identify the active substances. Kennaway and his colleagues isolated and identified, in 1930, the first known oncogenic substance which was dibenzoanthracene, a polycyclic aromatic hydrocarbon. The cancerogenic agents that are chemical elements will of course cause cancer, but only when the appropriate, characterizable terrain exists in the organism; otherwise no cancer will result.
Other similar oncogenic substances were quickly found and identified, some of which are so powerful that micrograms are enough to produce shin cancer when applied to appropriate experimental animals. These oncogenic substances are liposoluble and often have an apparent similarity to some steroids; thus 3-methylcolantrene, one of the most powerful cancerogenous substances, has a certain estrogenic effect. Polycyclic aromatic hydrocarbons are among the agents that have best been studied, but their action is quite poorly understood. These hydrocarbons can produce localized tumors in any tissue with which they come into contact, in rodents, except for the liver because this organ possesses the indispensable enzymatic mechanisms for metabolizing hydrocarbons into inactive metabolites.
On the other hand, other oncogenic agents act on a much smaller number of tissues, characteristically, in regions far from the sites where they are applied. In general, if the oncogen has to be specially biotransformed to act as one, the number of tissues sensitive to its action will be greatly reduced. Some aromatic amines are good examples, particularly 2—naphthaline, used in the dye industry. When this amine is inhaled or absorbed through the skin by workers, it produces cancer in the epithelium and in the bladder. Aromatic amines are in— active in and of themselves and need to he converted into oncogens in vivo. It has been demonstrated that a metabolic step necessary for this is N—hydroxylation which can be carried out in the vesical epithelium. The derived synthetic N-hydroxylate can produce, according to Tiller and Miller ( 1969) , local tumors more easily when applied subcutaneously, than the original compound.
There is a great variety of compounds that have, -to a greater or lesser degree, oncogenic properties and they arc of considerable practical importance when found as food contaminants or industrial residues. There is no doubt that our ecosystem, as it becomes more and more contaminated by technology, contains oncogens in ever—increasing numbers.
The oncogenic risk of tobacco has recently attracted great interest. The dangers of tobacco tars have been widely recognized in the last few decades, though since 1795 Soemmering had already noticed the correlation between pipe smoking and lip cancer. Epidemiological proof now shows quite clearly that cigarette smoking causes squamous epithelial, bronchial, and it is possible that it plays a role in the development of bucal and laryngeal cancer, as well as cancer of the kidneys, esophagus, and bladder. The interactions of tobacco oncogens arid other factors, however, have not yet been clarified.
In 1961, two cases of epizotia were caused by environmental oncogens. In the first, the ingestion of cocoa flour killed, by hepatic intoxication, thousands of baby turkeys, ducks and chickens in England. The other case was one where alimentation was said to have caused an epizotia of hepatomas in trout hatchery workers in the northeastern Pacific. It was later found that both cases were due to the contamination of food with Aspergillus flavus and four aflatoxins were isolated from -the contaminated food. These aflatoxins are the most active hepatocarcinogens known; they are much more effective than the aminoazoic dyes that are used as the standard laboratory hepatocarcinogens. It is possible that the hepatocarcinoma and the gastric carcinoma can sometimes be attributed, in man, to the aflatoxins contained in some diets.
Modern habits of alimentation are one of the important patterns in the cause of cancer; this can be clearly seen given that the whole organism feeds on the chemical elements that through digestion are derived from the foods we ingest. If these are riot appropriate, then with the passing of time they will contribute to the creation of cancer—prone terrain. If this terrain is not present, then tobacco will not cause cancer; otherwise it will most probably lead to cancer.
It is known that some hormones act to assist the oncogenic activity of other agents, but there is evidence that hormonal imbalance can provoke neoplasia in the absence of other, known, oncogens.
Radiation, and particularly ionizing radiation, can also have an oncogenic effect. It is well known that among the first radiologists numerous cases of chronic ulceration were observed that later progressed to carcinomas of the squamous cells of the hands and fingers.
Without a doubt, many neoplasias have been caused by doctors. For example, children treated with radiation therapy of the neck for reducing hypertrophy of the thymus, showed at a later stage of life, an unusually high index of thyroid carcinoma. In the same way, patients with the Naric-Strumpe syndrome, a rheumatoid arthritis of the spine, were treated, in the past, with radiation therapy which increased the frequency of lymphomas The small doses of radiation administered in the diagnosis of complicated’ obstetric cases can produce, according to the most recent evidence, an increment in the frequency of leukemia of children that were irradiated in utero.
The osteogeneous sarcomas that appear in painters of luminous watch dials indicate that radiation exposure can be an occupational hazard. It has also become a danger of war, as can be shown in the increment of leukemias in the survivors of Hiroshima and Nagasaki The lymphatic and bone marrow systems seem to be most; sensitive to radiation The mechanisms by which ionizing radiation causes neoplasias arc unknown but radiation is a mutagen. that induces aberrations in genetic structure; it also inhibits the immunological defense mechanisms, especially the physico—chemical ones——as in the case of chemical carcinogens——and produces destruction of cells and. compensatory hyperplasia, particularly in the lymphatic and bone marrow systems causing a bio—physico—chemical imbalance.
Besides ionizing radiation, there is another kind of energy that can be carcinogenic in man: ultraviolet radiation. The fact that many cases of skin cancer result; from exposure to it is well known. The biologically active wavelengths, that is those that produce neoplasias are the same ones that can destroy the skin and produce sunburn; they range from 2900 to 3200 A°. Given that the pigmentation of the skin with melanin is a protective measure, the incidence of skin cancer is less in people who are more intensely pigmented. The ostensive effects of the aging of the skin are the result, to a great degree, of exposure to ultraviolet radiation, more than aging in itself. In view of this and of the ease with which Vitamin D can be obtained from other sources, the healthy appearance of a sun tanned person (by exaggerated exposure to ultraviolet radiation) should he avoided, because it fosters aging of the skin and oncogenesis.
Neoplasia, with some exceptions, appears as a direct function of ago. In men, for example, the probability of the appearance of a prostatic carcinoma grows exponentially until reaching almost 100% in the aged. A similar relation is found for gastric, bronchial and mammary carcinomas; however, in these neoplasias the slope of the curve is not so marked. In mammary carcinomas the curve shows a definite hump (increase) around the age of menopause.
Though cancer is intimately related to aging, ‘there are some forms of cancer ‘that are specific to childhood, among which we find infantile leukemia, neuroblastoma, Wilms' tumor, and retinoblastoma.
The reason for the intimate relationship between neoplasia and old age is not known, but perhaps could be due to the fact that the neoplastic cell evolves through a series of accumulated aleatory alterations. On the other hand, there is less of an immune response in the aged. According to how ‘the individual ages, cell intoxication can increase, thus favoring the development of cancer.