EMBRYOLOGICAL ASPECTS AND ETIOLOGY OF CARCINOMA: GATEWAY TO THE CANCER STEM CELL THEORY
At the outset of his 1902 publication in the Lancet, Dr. John Beard discloses that as an embryologist he is not the most socially licensed scientist to be proposing a theory regarding the etiology of cancer. He advises that it is the current protocol for this subject matter to be left to the surgeons and pathologists, as it is concerned with dying, not of coming-into-being. Beard boldly notes that these professionals had thus far failed to define the cause of cancer. He goes on to reason that an embryologist may have more success at this task, as cancer is ultimately concerned with the appearance of something new and not the death or decay of something already present. Although his theory would not be widely accepted at the time, he ultimately would pave the way for a new breed of scientists to look at the ‘cancer problem’ from a radically different perspective. In this regard, the recently popular and broadly acknowledged stem cell theory of cancer is changing the way research is performed, and will ultimately change both the diagnosis and treatment of cancer.
As an embryologist, Beard first became attracted to the nature of cancer when learning about embryomas. These are tumours that arise in the fetal tissues and include Wilms tumours and teratomas. Wilms tumour is a renal tumor affecting one or both kidneys and is usually diagnosed between the ages of 2 and 5. It has become an important disease in modern medicine because of the lesson it teaches regarding the link between organogenesis and oncogenesis. It was important to Beard because the age of onset was dramatically different than what was normally seen in cancer; it contradicted the existing assumption that cancer was a disease of old age. Beard also fascinated himself with teratomas, a benign or malignant tumor that can recapitulate any tissue of the body. These tumours are certainly derived from multipotent cells as they, by definition, contain tissues from two or more of the three germ-layers. Most commonly present in the sacrum, ovaries, and testis, these tumours produce feelings of fear in many individuals as they frequently include bone, hair, teeth, fat, neural tissue, skin, and muscle. To Beard, embryomas scream to the nature of cancer as being a problem evolving from embryological development that can occur at any age.
The observations that Beard gathered to help form his trophoblastic theory of cancer came primarily, but were not limited to, studies performed in elasmobranch fish. His standpoint was that the nature of cancer could not be accurately described until the existing misunderstanding of the life cycle were dispelled. He refers readers to ‘Hereditary and the Epicycle of the Germ-Cells’, a German publication from the same year for an explanation of the life cycle. Briefly, it describes the life cycle not using the simplistic virtue that a hen lays an egg which develops into a hen which then lays another egg, thus completing the cycle. Rather, animal cycles are akin to that of a flowering plant where passage from egg to egg requires the existence of an asexual and a sexual generation. In humans, the asexual being arises after fertilization of an egg with a sperm. Following maturation, the asexual being is able to give rise to another gamete within its own tissues; this is what will contribute to further generations. He equates the asexual being to larvae in lower vertebrates and it is this stage that is key in deciphering the origin of cancer.
After fertilization, a single diploid zygote is formed which then undergoes three asynchronous divisions to reach the eight-cell stage. The next division results in the formation of the morula; this is where the first differentiation occurs as the outer layer of the cells adopt an epithelial structure referred to as the trophoectoderm. The inner cells will continue to divide until a second differentiation step occurs where the inner cell mass gives rise to the epiblast and the primitive endoderm. The epiblast will continue on to form the embryo itself and the primitive endoderm converts into a nutrient source as the yolk sac and also contributes to pattern formation in the embryo. The trophoectoderm differentiates to form trophoblast cells, which make up the non-maternal components of the placenta. During the fifth week of human development, the germinal ridge along with the sex cords begin to develop which later go on to form the gonads in both males and females. Primordial germ cells (future gametes) migrate from the yolk sac, up through the hindgut and to the germinal ridge where they incorporate into the sex cords and begin to differentiate and expand. It is these primordial germ cells that Beard theorized to be the cause of all cancer in both young and old patients.
Theoretically, every single primordial germ cell that is produced has the potential to give rise to a sperm or an egg, and thus a new organism if the opportunity arises. It is this potential that lead Beard to speculate that the embryomas described above must arise from persistent primary germ-cells. Beard used his observations from the elasmobranch family of cartilaginous fishes to demonstrate his hypothesis. Previous studies had established the theoretical number of primary germ cells that should be present in any given organism using a mathematical equation. The dog-fish was postulated to have 127 primary germ cells present at the germinal ridge. However, through pain-staking microscopic analyses, Beard established that there were only ever 90-100 primary germ cells present at the germinal ridge; the remainder were scattered in all sorts of unusual places. Beard examined a variety of species and never saw any example where the primordial germ cells were all in their proper position. These vagrant germ cells are normally decrepit, degenerating shortly after deposition. Occasionally these cells will persist in a viable state. These enduring germ cells rarely, if ever, continue on their path to the germinal ridge. Thus, as all germ cells have the potential for growth, any expansion of these vagrant cells will lead to the development of a product other than an embryo in a location other than the gonads. He equates the growth of these vagrant cells to the stage of the asexual being, or the larvae, with unrestricted growth potential. By way of definition, this is what is known as a tumor regardless of its classification as benign or malignant.
Beard has found vagrant germ cells to be located most commonly in the intestines, kidneys, liver, stomach and skin. Less often, they are seen in the head and the pericardium. These are some of the most common regions for cancer formation that were seen at the beginning of the twentieth century. Recently, the leading causes of cancer death have changed due to environmental insults such as smoking and increased age, but the above cancers are still quite common. At the time of this publication, oral-esophageal and mammary cancers were also frequently seen. However, Beard had no direct observational evidence of vagrant germ cells being present in these areas. To clarify this discrepancy, he explained that germ cells can reach these regions in the areas where folds and layers of tissues come together during embryogenesis and essential create ‘holes’ through which vagrant cells can pass. Although plausible, but highly speculative, Beard needed to incorporate this explanation for the development of other common cancers in areas where vagrant cells are not seen to ensure that the viewpoint of the day, suggesting that there can only be one cause for cancer, was satisfied.
Throughout this publication, Beard fully admits that his theory is based wholly on observation and is inferred from the facts presented to him from his work as an embryologist. Unfortunately, the very nature of the hypothesis is such that it could not be confirmed through direct observation and his ideas remained largely unaccepted by his peers. Currently, it is acknowledged that some malignancies, namely teratomas, do in fact result from vagrant germ cells that have arrested in the course of their passage to the germinal ridge and have later reactivated culminating in the formation of a carcinoma.
The most important implication of Beard’s theory for the development of cancer arose in the second half of the twentieth century and to this day remains hotly debated throughout the scientific community. This was the evolution of the ‘cancer stem cell’ theory and was only able to come into being after the discovery of somatic stem cells in the haematopoietic system, and subsequently other tissue types. A stem cell is characterized by the capacity to differentiate into multiple cellular lineages and to self-renew in an undifferentiated state. This definition has caveats depending upon the type of stem cell and the location of the cell within the body. The majority of the cells within an early embryo will eventually differentiate giving rise to the stem cell compartments which then form and maintain somatic and germ line tissues in the adult organism. It has been definitively shown in acute myelogenous leukemia, neuroblastoma and now breast cancer, that only a small subset of cells in a tumor are able to proliferate and form a tumor in a new host. This tumorigenic subset of cells is referred to as the cancer stem cells and are considered the only ‘hazardous’ cells in the tumor; the rest are just differentiated cells that are taking up space. This is beginning to revolutionize the way people think about designing cancer therapy as only this small subset of cells will need to be eliminated in order to ablate a tumor. These cells pose the largest problem to clinicians as they are more chemoresistant than the bulk of the tumor cells and are thus harder to eradicate. Many groups believe that these cancer stem cells arise from normal stem cells that have lost some crucial regulatory factor and thus gain the capacity for indefinite replicative potential. Although slightly removed from Dr. Beard’s original proposal, this theory has created great controversy and insight into modern medicine and has evolved as our knowledge base surrounding developmental biology increases. In fathering the cancer stem cell theory, Dr. Beard may also have alluded to another valuable point originally published in his Lancet article; perhaps cancer research is indeed better left in the hands of the embryologist.
References:
Beard, J. Embryological aspects and etiology of carcinoma. Lancet 1902; 1: 1758-1961.
Beard, J. Hereditary and the Epicycle of the Germ-Cells. Biologisches Centralblatt 1902; 22: 321-408.
Martin, L.C., D. Papadatos, C. Michaud, and J. Thomas. Liver teratoma. RadioGraphics 2004; 24: 1467-1471
Ralston, A. and J. Rossant. Genetic regulation of stem cell origins in the mouse embryo. Clin Gent 2005; 68: 106-112.
Reya, T., S.J. Morrison, M.F. Clarke, and I.L. Weissman. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-111.