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Home > Health Knowledge Base > Cancer Information > The Unitarian or Trophoblastic Thesis of Cancer

The following is the classic monograph by the Krebs and Beard, which was submitted to the Medical Record in 1949, and then published in 1950. This is only one of an expanding series of essays and monographs by Dr.Krebs and associates about the science of cancer and its rationale treatment utilizing metabolic and dietary protocols: specifically, empowering the endogenous pancreatic enzymes, and/or supplementing same; and the dietary inclusion of nitrilosides, the specific antineoplastic compounds found ubiquitously in nature, but hardly at all in the common faire of civilization.

THE UNITARIAN OR TROPHOBLASTIC THESIS OF CANCER

by Ernst T. Krebs, Jr.,* Ernst T. Krebs, Sr.,**
and Howard H. Beard***

(Reprinted From the Medical Record, 163:149-174, July 1950)

It is veritably impossible to find, among the hundreds of valid experimental contributions to our knowledge of cancer made during the past half century, an experimentally established datum that would controvert the thesis of the basic biological uniformity characterizing all exhibitions of cancer.

THE CRITERIA OF UNIFORMITY

To the experimentalist who does not overtly accept an unitarian thesis of cancer, such a thesis is still implicit in the commonplace facts of his science. The classic experiments of Warburg on the respiratory pattern of cancers of various species and tissue origins reveal a high uniformity from tumor to tumor.¹ Correlatively, the Coris find the lactic acid and sugar content of the various exhibitions of cancer to be highly uniform.² Williams and his co-workers report a pronounced degree of uniformity in the concentration of eight B vitamins in a great variety of animal and human tumors, regardless of the tissue of origin or the manner of their induction.³ Robertson makes similar observations for vitamin C.⁴ The addition of various substrates to malignant tumors of various types yields highly uniform respiratory responses.⁵ Shack describes an almost complete uniformity in cytochrome oxidase content in a number of mouse tumors. ⁶ Greenstein finds that the presence of any exhibition of cancer uniformly results in a depression of the liver catalase. ^7,8 Maver and Barrett describe substantial evidence for an immunological uniformity among malignant tumors.⁹ Greenstein reports an impressive degree of uniformity in enzyme concentration among malignant tissues, regardless of their means of induction, tissue of origin or species of origin. ¹⁰ Others describe a uniformly low content of such aerobic catealytic systems as cytochrome, succinic, and d-amino acid oxidases, cytochrome-c, catalase and flavin.^{11,12,13,14,15,16,17}

Further phenomena of uniformity are observed in the elevated water and cholesterol content of malignant tumors as well as other primitive tissues.^18,19 The induction by a single steroid carcinogen, such as methylcholanthrene, of malignant exhibitions as diverse as leukemia and malignant melanoma, attests to a basically uniform etiology. The uniformity of various exhibitions of cancer in respiratory properties, lactic acid production, vitamin content, enzyme content, action on a given substrate, effect on liver catalase, cytochrome oxidase content immunological properties, and many other characteristics is correlative to an uniformity of

malignant tumors in the ability to metastasize, in their amenability to heterotransplantability, ^{21, 22} and in their autonomy, invasiveness and erosiveness. Indeed, there is no known basic property unique to any single exhibition of cancer---the only variation being a morphological one partially conditioned by admixed benign or somatic components.

The degree in the uniformity of the factors described increases with the increasing malignancy with which the tumor is exhibited. Thus with an increasing degree of malignancy, all malignant exhibitions converge toward a common tissue type. For this reason the cells of the most malignant of all exhibitions of cancer should epitomize the properties of the malignant component in all other exhibitions of cancer. That this is the case, we shall observe in the pages that follow.

We have glanced briefly at data that are commonplace to cancer research. The logical consequences of these data have, however, seldom been examined. Since the phenomenon of cancer is truly an unitarian one, then, of logical necessity, the variations in the biological malignancy of different exhibitions of cancer must be a function of the concentration of a cell of an intrinsically uniform malignancy.

POSITION OF THE CANCER CELL IN THE LIFE-CYCLE

In accounting for the nature and origin of the single cell type comprising the constant malignant component in the varying morphological exhibitions of cancer, we find one of two alternatives open. The definitively malignant cell either has its normal counterpart in the life-cycle or the malignant cell is without a normal cellular counterpart and, therefore, arises as a spontaneous generation. Since spontaneous generation is an untenable postulate, the only alternative is that the malignant cell has its counterpart in the life-cycle. The question then arises whether this counterpart is a relatively developed cell or the most primitive cell in the life-cycle. Since the primitivity of the cancer cell is a commonplace, in looking for its cellular counterpart in the life-cycle we turn to the most primitive cell in this cycle. This is the trophoblast cell. Then as a logical corollary of the unitarian thesis, we should find the trophoblast as the constant malignant component in all exhibitions of cancer: the malignancy of the cancer varying directly with its concentration of trophoblast cells and inversely with its concentration of somatic cells.

If the unitarian thesis is valid, then the most malignant exhibition of cancer possible should be comprised almost completely of frank trophoblast cells; and, in being so comprised, should epitomize the cellular and other phenomena shared by exhibitions of a lesser malignancy. The most highly malignant exhibitions of cancer known are the chorionepitheliomas comprised of frank trophoblast cells, cytologically, endocrinologically and otherwise indistinguishable from normal pregnancy trophoblast cells. If cancer is an unitarian phenomenon whose malignancy is a function of the concentration of trophoblast cells within a given tissue, then the greater the concentration of such cells within a tissue the higher the malignancy

of the tissue and the more profound its cytological deviation from the cytology normal to the tissue. If the unitarian thesis is valid, then the single exception to this generalization would comprise the most malignant of all exhibitions of cancer: that involving the pathologic exhibition of the normally or "physiologically" malignant pregnancy trophoblast. It is, therefore, most significant that when pregnancy trophoblast is malignantly exhibited as primary uterine chorionepithelioma there is no ascertainable cytological, endocrinological or other intrinsic change whatever from the normal trophoblast cell. As Boyd has phrased it, "microscopically the chorionepithelioma is an exaggeration of the condition normally found in pregnancy."²³ All other tumors represent an attenuation of the condition of their normal tissue of origin.

PROPERTIES OF THE TROPHOBLAST CELL

But if cancer is, as an unitarian phenomenon, trophoblastic then we should expect to find occasionally in the male---where trophoblast never normally exists---at least some cases in which the failure in somatic resistance to the definitive malignant cell (trophoblast cell) is so complete that the trophoblast is frankly exhibited as such in the fiercely malignant testicular or primary extra-genital chorionepitheliomas.^{24, 25, 26, 27, 28} The chorionepitheliomas are unquestionably the most malignant tumors in either sex, and the degree of their malignancy is routinely determined by measuring the gonadotrophin their trophoblast cells excrete.^{29, 30, 31}

If the trophoblast cell, presented outside the normal canalization or checks of pregnancy, is truly the cancer cell, then it must be impossible for the trophoblast cell or its hormone---"chorionic" gonadotrophin---ever to be found in the male or, aside from the canalization of normal pregnancy, in the female except in a malignant fashion. Neither the trophoblast cell nor its hormone has ever been so found except as cancer. And whenever the trophoblast cell or its hormone has been found in the male or the non-pregnant female, the associated malignancy is observed to vary directly with the urinary excretion of trophoblast cell-produced gonadotrophin.

Even a superficial examination of the trophoblast cell indicates that it possesses such properties of the cancer cell as invasiveness, erosiveness, autonomy and ability to metastasize throughout the organs of the host.^{32, 33} Indeed, though normally canalized to physiological ends, the pregnancy trophoblast in carrying the conceptus from anatomically outside of the maternal host to implantation within the uterine wall must behave in a profoundly malignant fashion. No malignant cell invades any tissue any more rapidly and completely than the pregnancy trophoblast does the human uterus in the first few weeks of gestation.

If the trophoblast cell, then, is instrinsically malignant, this malignancy should become especially apparent when the trophoblast is removed from the normal extrinsic checks and controls surrounding it in its normal canalization of pregnancy. Maximov is among those who have observed normal pregnancy trophoblast in tissue culture pari passu non-tropho-

blast.³⁴ He describes as follows a tissue culture preparation of a normal rabbit embryo plus the contiguous trophoblast:

"From the very first moment of their formation in vitro, the trophoblastic elements, whose function under normal conditions is to destroy, resorb, and penetrate into the uterine mucosa, attack the growing embryonic tissues. They glide between cells through the intercellular spaces, along blood vessels, gnaw large holes in epithelial sheets....Wherever they appear they dissolve, destroy and resorb everything surrounding them. The picture sometimes bears a striking resemblance to chorionepithelioma malignum. As in vitro there is no maternal tissue, the destructive tendencies of the trophoblast are directed toward the net and only available---the embryonic tissue itself. This is rapidly destroyed and totally used up for the nutrition and growth of the trophoblast."

Maximov's description of the nutritive utilization by the trophoblast of somatic or embryonic tissue in vitro bears a striking parallelism to the following observation of Greenstein³⁵ on the nutritive behavior of the cancer cell:

"It is, indeed, astonishing that a tumor can thus attach itself to an organism already running downhill in negative nitrogen balance and subsequently grow at the host's further expense."

Parasitization is eloquently clear in the description given by Maximov and it is implicit in Greenstein's observation. Normal pregnancy trophoblast represents, of course, a parasitization of cells of one genetic constitution by those of another. If cancer is an unitarian and thereby a trophoblastic phenomenon, its parasitic behavior is very easy to understand.

Were pregnancy trophoblast in vivo or in situ to lack the humorally mediated checking influences that are lacking in vitro then such tissue would expectedly behave as it does in vitro and be exhibited in the fiercely malignant fashion of primary uterine chorionepithelioma.

Rather than pause here to review in further detail the points of identity between the cancer cell and the trophoblast cell, of which the senior author in a review of over 17,000 papers has been able to catalogue 43, let it suffice to say that we have been unable to find a single point of dissimilarity between the cancer cell and the trophoblast cell. The points of identity, of course, are those shared exclusively by the cancer cell and the trophoblast cell and not shared by any somatic cell.

THE CELL OF ORIGIN AND THE MEANS OF ITS DIFFERENTIATION

If cancer is a truly unitarian phenomenon, then its cellular origin as well as its cellular nature are exemplified in the origin and nature of the most malignant exhibition of cancer---primary uterine chorionepithelioma.

Pregnancy trophoblast arises through the differentiation by meiosis of a diploid totipotent cell in response to organizer stimuli (afforded through the sex steroids). The meiosis of the diploid totipotent cell results in a haploid gametogenous cell whose only alternative to death is division (sexually or parthenogenetically induced) with the consequent production of trophoblast. The only cell from which the most primitive cell in the life-cycle, the trophoblast cell, can arise is the most undifferentiated or

most potent cell in the life cycle: the diploid totipotent cell. It is this cell alone that is competent for meiosis. In fact, aside from the explanation of spontaneous generation, only two alternatives exist for the origin of the malignant cell. Like all other growth phenomena, it may arise as the result of the differentiation of an undifferentiated cell in response to organizer stimuli; alternatively, it may be ascribed to the ontogenetic "reversion" of normal cells to a primitive state. Even though the very notion of such reversion is a thermodynamic fantasy inadmissible by modern biology, if a normal cell could revert, the most primitive cell in the life cycle toward which such reversion could occur is still the trophoblast cell. Hence, aside from the errors of spontaneous generation or cellular reversion, only the phenomena of cellular differentiation are tenable in accounting for the origin of the cancer cell---though the stimulus to such differentiation may, of course, be diversely mediated.

It is thus a simple embryological fact that the malignant component of the most malignant of all exhibitions of cancer---primary uterine chorionepithelioma---represents the unchecked growth of normal trophoblast that has arisen through the differentiation of a diploid totipotent cell, by reduction division, and the division of the consequent haploid gametogenous cell to produce trophoblast. We have seen the proof of this in the fiercely malignant behavior of rabbit trophoblast removed from the checking influences of the maternal host and placed in tissue culture. This trophoblast, of course, came into being through processes normal to the production of all trophoblast in normal gestation. This is true also of the trophoblast of primary uterine chorionepithelioma.

It is necessary that we emphasize here the fact that our description of the origin of any trophoblast cells is merely a recapitulation of commonplace, universally accepted embryological data. We must not permit terminology to obscure this fact. Let us add that it has been experimentally established that in mammals the haploid gametogenous cell in either the male or the female may be nonsexually activated into division with the consequent and inevitable production of trophoblast.

Because the trophoblast cell of primary testicular chorionepithelioma is indistinguishable from that of the normal pregnancy trophoblast cell^{36, 37, 38} or a trophoblast cell of primary uterine chorionepithelioma,^{39, 40} the general consensus in pathology that chorionepitheliomas arise from the division of a gametogenous cell (non-sexually activated), derived through the normal meiosis of a diploid totipotent cell, is biologically and logically sound. It is likewise generally recognized that primary extra-genital chorionepitheliomas occurring in both sexes represent trophoblast that shares a common cellular origin with all other trophoblast; an origin from an haploid gametogenous cell (through fertilization or non-sexually) that has arisen through the meiosis of a diploid totipotent cell. This principle is congruent with the axiom that cells which are alike arise from pre-existing cells that are alike.