Identity of the Cancer Cell
Bishop and Varmus received the Nobel Prize in medicine (1989) for, in effect, showing that cancer is encoded (through what they chose to call oncogenes) in the animal life-cycle: that it is not a spontaneous generation. Like all other facts, this one carries implicitly the iron exaction of reason, of logic.
Since cancer is not spontaneously created but is one with a cellular counterpart in the normal life-cycle, what is the spatial and temporal counterpart of this entity in the mammalian life-cycle? Is it the most primitive, the least primitive or an intermediate in the primitivity of this cycle? Does its encodement in the life-cycle represent a genotype without an actually realizable normal phenotype?
The most primitive or earliest cell in each genetically unique mammalian life-cycle is, of course, the trophoblast cell. A major function of the trophoblast cells is to erode, infiltrate, digest and destroy selectively, all non-trophoblast cells in the process of bringing the genetically unique conceptus (trophoblast + definitive embryo) into the tissue of the maternal or somatic host. At the point of penetration or contiguity with the tissue of its host, the trophoblast is hybridized with and vascularized by such a host to the extent that only electron microscopy suffices to distinguish visually the heterotransplant from the hostal or somatic cells as well as both from the trophoblast-soma hybridized cells produced.
There are over 92 attributes enumerated (and referenced) for the identity of trophoblast and the cell called a cancer cell - and with none of these attributes shared elsewhere in the mammalian life-cycle. Such trophoblast is, of course, brought into being through normal cellular differentiation responding to the organizer action of estrogen.
All trophoblast, whether in the implantation site of the uterus or ectopically, comprises at the immediate point of invasion or contiguity a hybridization with hostal or somatic cells that leaves the invading trophoblast at the point of contiguity largely indistinguishable from the hostal or somatic cells. This hybridization occurs in normal gestation (spatial and temporal congruity) as well as trophoblast in spatial and temporal anomaly (cancer).
The concrete and specific deflation of canal then, becomes:
"Cancer is trophoblast in spatial and temporal anomaly hybridized with and vascularized by hostal or somatic cells in an irreversible and fiercely malignant antithesis one to the other of such."
This is the uncontradicted (and apparently uncontradictable) unitarian or trophoblast fact of cancer. Any attempted contradiction or alternative definition of cancer will devolve into reduction ad absurdurm.
Though the intrinsic biological malignancy of trophoblast is fixed and inalterable, the clinical exhibition of its malignancy is proportional to (1) the spatial and temporal appropriateness of its site of heterotransplantation, (2) the hostal acceptance and control of the heterotransplant, and (3) the rate and extent of overgrowth of such unhybridized trophoblast as conditioned by (1) and (2). A frank overgrowth of unhybridized trophoblast elements is obligatively cancer (trophoblast in spatial and temporal anomaly).
While it is not practicable to attempt to cite a supporting bibliography from our derisive work The Science of Cancer, (275,000 words, 18,000 + references), we make an exception here in citing Alexander Maximov's monograph on "Tissue Cultures of Young Mammalian Embryos" from Carnegie Contributions to Embryology, 16, 47, 1924.
Maximov's opening paragraph reads: "The cultures of the youngest embryonic stages of the rabbit have in the majority of cases, a very peculiar fate. This is in consequence of the fact that...however carefully the embryo may be excised out of the wall of the blastodermic verde there still remains, as a rule, a small particle of the surrounding ectoplacental trophoblastic area attached to the explant. This trophoblast remains in a latent condition and the embryo proper usually has time to attain a certain degree of development. Sooner or later, however, usually after 2 to 4 days, the trophoblast elements become active and change completely the condition of the growing explant."
Maximov continues: "...From the very first moment of their formation in vitro the trophoblast elements, whose function under normal condition is to destroy, resorb and penetrate into the uterine mucosa, attack the growing embryonic tissues. They glide between the cells through the intercellular spaces...Along blood vessels, gnaw large holes in the epithelial sheets. Wherever they appear, they dissolve, destroy, and resorb everything surrounding them."
After about 5 days in the culture chamber, the definitive embryo (conceptus minus trophoblast) is totally eroded, infiltrated and destroyed by the explosively growing contaminating trophoblast. Trophoblast, indeed, in spatial and temporal anomaly.
As late as 1924 Maximov was beset by our failure in biomedicine to recognize the fierce antithetic dichotomy between trophoblast, on the one hand, and the somatic or hostal definitive embryo, on the other. He was left, in effect, to describe "embryonic trophoblast" attacking "the growing embryonic tissue." His use of the phrase "embryo proper" was engendered, of course, as an expedient borne of our ignorance then of the profound antithesis existing between the trophoblast, on the one hand, and the definitive embryo or soma, on the other. There simply was no new and indispensable terminology yet to accommodate the new and implicitly revolutionary reality.
As is retrospectively apparent now, the successful completion of the span of gestation of the rabbits Maximov studied necessitates the resolution of its precedent, fiercely antithetic trophoblast. This reality is paradigmatic for all mammalian gestation.
It was not until 1885 that A.A.W. Hubrecht, in his study of the placentation of the hedgehog (Erinaceus europaeus) saw that there is an unique or distinctive tissue, which, as discoverer of it, he named trophoblast. This is an entity theretofore unknown to exist as such or as its homologues in any animal life-cycle. It exists in the animal life-cycle even prior to what Krebs, Jr. explicitates as "the definitive embryo." Hubrecht used the term trophoblast for the first time before the Anatomical Society of Wurtzburg in 1888. Then in the opening century less than a decade lair when the physical nor anatomical reality of the trophoblast (not its function, physiology or biochemistry) became vaguely known among some comparative "embryologists," it was not correlated or integrated with the animal life-cycle, but rather implicitly added or appended descriptively to what we now describe as "the definitive" embryo. This new "embryonic" bit was appended with the unexamined assumption that the higher levels in the ontogeny of the real or actual embryo arose through the differentiation of the precedent trophoblast in the life-cycle. This false conclusion, let us note, is of the imperishable logical fallacy of post hoc, ergo, proper hoc - after this, therefore because of this. Not always so! as every magician knows.
With his discovery of the trophoblast Hubrecht ventured the highly plausible and quickly accepted guess that the function of the trophoblast was to nourish the embryo. This guess is totally wrong. Maximov in 1924 unwittingly showed, to his expressed dismay, that the trophoblast actually nourishes itself by selectively feeding on the embryo, digesting and consuming the embryo or soma. By 1902 John beard, the even then famed comparative embryologist of the University of Edinburgh Medical School, showed that carcinoma is trophoblast (Lancet June 21, 1902) and then in 1904 that sarcoma (Lancet, October 29) is trophoblast - the unitarian or trophoblast identity of both.
Hubrecht, in naming the trophoblast embalmed his error on the mistaken nutritive function of it etymologically. "(Tropho - trof'o) (Gr trophe nutrition) a combining form denoting relationship to food or nutrition," Dorland's Illustrated Medical Dictionary, 27th ed, p 1401. The word, unfortunately, became the concrete thing, the error.
This critical error - the failure to recognize the fiercely antithetic dichotomy between trophoblast, on the one hand, and the embryo or soma, on the other, sealed or foreclosed for almost a century now, the identity of cancer or the cancer cell.
Like all other cells in the life-cycle of plants or animals, trophoblast can arise only through the differentiation of less differentiated cells responsive to organizer stimuli. Since estrogen is normally and specifically the organizer for trophoblast differentiation, it is clear why "natural selection" could not have excluded this "carcinogen" from the animal life-cycle.
Describing the inadvertent and usually unavoidable contamination of his rabbit embryo cultures by a microscopic bit of the precedent conceptual trophoblast, Maximov wrote: "...The picture sometimes shows a striking resemblance to chorionepithelioma malignum. After six days of life in vitro only a vast syncytium remains of the whole culture. This (definitive embryo) is rapidly destroyed and totally used up for the nutrition and growth of the trophoblast."
We note the qualifier sometimes. Within the span of such growth in the culture chamber (i.e., trophoblast in spatial and temporal anomaly, almost every known neoplastic exhibition, including chorionepithelioma, is manifest. This exhibition is almost pure trophoblast; hence the most malignant of all possible exhibitions. However, the countless pleomorphic forms exhibited by the trophoblast in vitro were always sufficiently vital to account for the total consumption of the non-trophoblastic or somatic definitive embryo. We note that Maximov non-reflectively - blind to Hubrecht's critical but honest error - told it as it is:...The definitive embryo "is rapidly destroyed and totally used up for the nutrition and growth of the trophoblast." Trophoblast selectively consumes or cancerizes non-somatic, hostal definitively embryonic tissue. It nourishes itself by consuming somatic or hostal tissue rather than ever nourishing such. The selective vulnerability or susceptibility of somatic or non-trophoblast tissue is uniform from the earliest definitive embryo (as Maximov's cultures showed) to the soma of the most senescent person.
In the course of its own successful gestation, every mammal destroys the cellular counterpart of cancer, its own trophoblast. This is because the hostal or somatic antithesis prevails. However, the host or soma is almost as malignant or "cancerous" in the digestion of the trophoblast as the trophoblast initially in the span of gestation is toward the host or soma.
The acid intracellular digestion by trophoblast of all that is not trophoblast (i.e., somatic or hostal) is highly virulent. The 1924 observation by Maximov corroborates the asservation of the likes of Bishop and Varmus that cancer is, indeed, encoded in the life-cycle. (The fallacy of any spontaneous generation dies hard). The encodement or genotype is realized in the phenotype of trophoblast whether or not it is growing In spatial and temporal congruity (gestation) or in tissue culture or elsewhere in spatial and temporal anomaly (cancer).
Growing in the spatial and temporal congruity of anatomically normal gestation, the trophoblast is delimited extrinsically by the tryptic alkaline extracellular milieu of its host. The vestiges of trophoblast so controlled are ejected mainly through parturition or spontaneous abortion. It is impossible for trophoblast to per, st and grow in hostal or somatic tissue (i.e., in spatial and temporal anomaly except as cancer. The clinical malignancy of such a process varies with the rate of growth (hence with the concentration of trophoblast), which concentration is conditioned by hostal or somatic antithesis to it. This is why trophoblast has NEVER been observed to grow in hostal or postnatal tissue except as cancer.
Though the identity of the trophoblast cell is fixed, the clinical malignancy of its exhibition is partially conditioned by the extent to which it is hybridized with hostal or somatic (i.e., non-trophoblast) tissue and brought partially into syncytial adaptation. Its chorionepitheliomatous exhibition is its most malignant one because such is largely pure or unhybridized trophoblast. There is nothing that can "cancerize" it. Cancer is but the expression of such growth in spatial and temporal anomaly. Around the 50th day in the span of human gestation trophoblast growth is such (as measured by the output into the blood and urine of chorionic gonadotrophin and five or more other glycoprotein hormones exclusive to trophoblast) that were such trophoblast growth to persist for another 60 or more days the foetal and maternal soma (bodies) would be killed in the most fiercely malignant exhibition possible. This is actually but an IN VIVO reprise of what Maximov described IN VITRO in 192 4 -- without possibly suspecting the profound significance of it all.
The trophoblast is the source of the tumor angiogenesis factor (TAF) of Judah Folkman that elicits vascularization from the host (at the point of trophoblast contiguity) and thus opens in the host metastatic pathways for trophoblast. The higher the level of trophoblast growth, the higher the production of TAF, and the greater the metastatic proclivity.
Folkman isolated TAF from cancer in man and other mammals. He found it also in the trophoblast-bearing placentas of such. TAF stimulates the growth of blood vessels from the host into the growing cancer, and gives the latter a way to rid itself of waste products. Trophoblast in spatial and temporal congruity (gestation) (1) elicits blood vessels (angiogenesis) from its host, (2) all trophoblast does whether in spatial and temporal congruity or anomaly, (3) trophoblast is the membrane through which all nutrients including oxygen from the host pass into the non-trophoblast of the "tumors," (4) through which membrane wastes pass to the host, and (5) without which TAF trophoblast can not implant and survive.
The genesis in the implanting and sustenance of cancer from our perspective is obviously an unitarian or trophoblast one. Dr. Folkman's findings are, in our opinion, potentially all-encompassing.
Experimentally, were grown the trophoblast of one mammalian species (i.e., of normal human placental tissue) with hostal or somatic cells of another species to produce virulent neoplasms of varying morphology. The trophoblast of a normal human placenta (any time within term), implanted into the anterior chamber of the eye of a rabbit has uniformly taken with avidity, grown to erode and infiltrate the tissue of its host as well as to be hybridized and vascularized by such. The TAF in such implants accounted for an extreme degree of hostal vascularization at the implantation site. Slides of such implants were diagnosed as cancer by pathologists We were initially puzzled by the avidity with which such in vitro implants grew until we recalled Maximov's complaints about the difficulty he found in avoiding trophoblast "contamination" of in vitro cultures of his rabbit embryos.
Maximov's frustration in attempting "however carefully' to excise the somatic or hostal embryo from the surrounding ectoplacental cone of the rabbit conceptus (almost pure trophoblast) is a failure frequently matched by that of the skilled surgeon who attempts to excise the trophoblast-rich neoplasm of a breast or prostate gland from its normal somatic or hostal context. "We got it all" is too often a hope, not a reality, of such attempt. The molecular biologist tells us that the encodement for trophoblast is in the genome of all cells. The organizer action of estrogen and/or its analogues will elicit the differentiation of this encodement into trophoblast "in spatial and temporal anomaly" (cancer). The more proliferative the somatic or hostal tissue, the greater is its disposition toward trophoblast differentiation - as well as differentiation in general. No trophoblast in pregnancy comes into being, and none is sustained after coming into being without estrogen inducing the di fferentiation into trophoblast and maintaining it in gestation. The syncytial aspect of the trophoblast produces estrogen and other steroid hormones.
The male rabbit hosts of the occular implant of human placental trophoblast excreted heavy urinary quantities of the chorionic (cytotrophoblastic) hormone, as well as other glycoprotein hormones exclusive to cytotrophoblast in quantities roughly proportionate to the vigor of the growth of the implant. This adumbrates the growing wide spread reports of from one to six trophoblast glycoprotein hormones exclusive to trophoblast found, at one time or another, in the tumors, blood and urine of hosts of every primary and secondary exhibition of cancer (including the leukemias).
The profound constraints of the absence of an adequate nomenclature and a more definitive systematization of the general nature of the unitarian or trophoblast concept of cancer is painfully obvious here. A clarification must await the expansion given by our forthcoming book on The Science of Cancer (275,000 words). However, our isolation on the trophoblast identity of cancer is neither daunting nor complete. In his scholarly and clinically oriented book on the Human Trophoblast (Charles C. Thomas, Springfield, Illinois, 1968) Arthur T. Hertig, then Chairman of the Department of Pathology at Harvard Medical School, did not let cancer preempt his magnificent systematization of "trophology," as he called it. But on the last of the 323 pages of his book, in the last sentence of the final paragraph he wrote:
"It has been fun for the author and his colleagues to have observed and participated over the years in the histologic and biologic sequence of events that truly make trophoblast God's first cancer and man's flint cure."
Trophoblast, whatever the extent of morphological masking by hostal or somatic tissue, is the constant malignant component in all exhibitions of cancer. This is the unitarian or trophoblast fact of cancer, for which any attempted alternative explanation will devote into reductio ad absurdum.
As medicine grows closer to the stern exactions of logic it will grow closer toward the science of mathematics. Here the reduction ad absurdurm criterion is the ultimate measure of the geometer and the mathematician in general in measuring or identifying a fact or truth. Euclid utilized this criterion circa 325 B.C.
Article copyright Townsend Letter for Doctors & Patients.
By Ernst Krebs