The Unitarian or Trophoblastic Thesis of Cancer - OAWHealth

The Unitarian or Trophoblastic Thesis of Cancer

The Unitarian or Trophoblastic Thesis of Cancer...

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 cell36,
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.

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