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The Trophoblast Model of Cancer a
Colin A. Ross a
The Colin A. Ross Institute for Psychological Trauma, Richardson, Texas, USA Published online: 05 Nov 2014.
Click for updates To cite this article: Colin A. Ross (2014): The Trophoblast Model of Cancer, Nutrition and Cancer, DOI: 10.1080/01635581.2014.956257 To link to this article: http://dx.doi.org/10.1080/01635581.2014.956257
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Nutrition and Cancer, 0(0), 1–7 Copyright Ó 2014, Taylor & Francis Group, LLC ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.956257
The Trophoblast Model of Cancer Colin A. Ross
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The Colin A. Ross Institute for Psychological Trauma, Richardson, Texas, USA
John Beard, the British embryologist and histologist, first proposed his trophoblast model of cancer in 1902. The model has subsequently been expanded by Kelley, and in current times, Gonzalez and Isaacs. The trophoblast model of cancer can be stated as a specified, scientifically testable model, including its core predictions that 1) adult stem cells are ectopic trophoblasts that have migrated to other tissues early in embryogenesis; 2) pancreatic enzymes are the key signal that converts the trophoblast into the stable placenta; 3) cancer arises from trophoblasts that have escaped regulatory control; and 4) pancreatic enzymes can be used to treat cancer. The author reviewed the literature on the trophoblast model of cancer and the use of pancreatic enzymes for the treatment of cancer and organized its key tenets into a set of specified scientific hypotheses. The trophoblast model of cancer can be stated as a set of 11 core predictions and 3 adjunctive or nonessential components. The trophoblast model of cancer is a detailed, testable model that should be investigated within an overlapping set of fields including oncology, histology, physiology, molecular biology, and embryology.
INTRODUCTION The trophoblast model of cancer originally developed by Beard (1), and refined by Kelley (2,3), Gonzalez (4,5), and Gonzalez and Isaacs (6,7), is a scientifically testable model. Beard was nominated for a Nobel Prize because of the quality and originality of his work in embryology. He was the first to identify adult stem cells. He was also the first person to propose that the corpus luteum inhibits ovulation during pregnancy, the first to describe the immunological functions of the thymus, and the first to describe cell apoptosis based on his histological studies of fish embryos. He also co-discovered the Rohon-Beard cells in the spinal cord (3). Beard (1) noticed that the transformation from trophoblast to stable placenta occurs at the same time as the pancreas appears in fetal development and begins to secrete enzymes. He therefore hypothesized that these enzymes, principally trypsin, are the Submitted 2 December 2013; accepted in final form 16 August 2014. Address correspondence to Colin A. Ross, The Colin A. Ross Institute for Psychological Trauma, 1701 Gateway #349, Richardson, TX 75080. Phone: 972-918-9599. E-mail: [email protected]
regulatory signal that controls this transformation. When this regulatory process fails, a choriocarcinoma develops. Another key observation of Beard’s was the existence of what he called wayward trophoblasts. He observed that about 15% of trophoblast cells are distributed throughout the body, where they reside in dormant form in different tissues and organs. In contemporary terminology, these ectopic trophoblasts are adult stem cells. Cancer occurs when, for unknown reasons, these adult stem cells escape normal regulatory control and begin to behave like normal trophoblasts do when they are forming the placenta: They invade, multiply, create their own blood supply, resist immune surveillance, resist cell adhesion, and remain undifferentiated compared to adult tissue and compared to the mature placenta. According to the trophoblast model, cancer cells are not dedifferentiated normal cells. Rather, they are normal trophoblasts that have escaped regulatory control and that take on some characteristics of the local tissue due to local signaling in the tissue. Thus, liver cancer cells look like dedifferentiated liver cells but are actually normal trophoblasts that have partially differentiated in the direction of liver cells. It follows from the model that the targets of cancer treatment should be a small population of dysregulated adult stem cells within normal tissue. The ability of trophoblasts to differentiate in the direction of neighboring normal tissue is well described by Bischof and Irminger-Finger (8): “Like a chameleon, CTB [cytotrophoblastic cells] are thus able to adapt to their immediate environment by phenocopying their neighbor cells.” The final step in Beard’s development of the trophoblast model of cancer was his prediction that trypsin could be an effective treatment for cancer because it would have the same effect on cancer cells as it does on embryonic trophoblast; it would cause the cells to differentiate, stop multiplying, stop being angiogenic, stop invading, and demonstrate normal cell adhesion. Whether or not the model is correct, it can be formulated as a specified, scientifically testable theory: Providing that formulation is the purpose of the present article. It is possible that some or many tenets of the model could be incorrect, whereas the treatment of cancer with pancreatic enzymes is effective for unknown reasons. 1
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The trophoblast model of cancer and models based on genetically driven dedifferentiation of normal cells are not mutually exclusive, even though Beard hypothesized that his model applies to all cancers. Given the complexity of biological systems and cancer, it seems unlikely that any one theory or approach could account for all cases. Even if correct, the trophoblast model does not specify all the regulatory signals and mechanisms involved and, most importantly, it is silent on the triggers that stimulate the escape of adult stem cells from normal regulatory control. These would presumably include known genetic and environmental risk factors for cancer. For example, perhaps the normal versions of the BRCA1 and BRCA2 genes (9) function to keep adult stem cells in the breast and uterus in a dormant state: the abnormal variants of the genes fail to perform this function and thereby allow the stem cells to escape control. BRCA mutations as risk factors are equally compatible with the trophoblast and normal cell dedifferentiation models of cancer.
CORE COMPONENTS OF THE TROPHOBLAST MODEL OF CANCER The core components of the trophoblast model of cancer as developed by Beard (1) and refined by Kelley (2,3), Gonzalez and Isaacs (6,7) follow.
THE SEXUAL–ASEXUAL ALTERNATION OF GENERATIONS IN PLANTS ALSO OCCURS IN MAMMALS Beard thought that the sexual–asexual alternation of generations in plants also occurs in mammals. It is an accepted fact in biology that plants and some lower animal species such as cycliophora, which lives in the mouths of lobsters, exhibit an alternation of generations (10). Generations, in this usage of the term, means that there are alternating multicellular haploid and diploid forms of a given species, such as cycliophora. In plants, the haploid or sexual generation is the gametophyte, whereas the diploid or asexual generation is the sporophyte. In animals, there is an alternation of generations in the sense that the diploid adult alternates with the haploid egg or sperm, but this is not an alternation of generations in the above sense because the haploid stage is unicellular. From an evolutionary perspective, the alternation of generations is conserved, but in higher life forms the haploid generation is unicellular. Considering this similarity between flowering plants and animals, it seems reasonable to say that there is an alternation of generations in mammals, as Beard thought, as long as one does not require a multicellular gametophyte. Beard wrote before DNA was discovered and before the terms haploid, diploid, meiosis, and mitosis had entered the literature. He believed, based on his careful histological observations, that the trophoblast gives rise to the embryo, which then matures to become the adult. In effect, the trophoblast
produces a single-cell spore early in development that becomes the embryo. Beard thought that the alternation of generations in mammals was exactly the same as in plants. This cannot be true because both the inner and outer cell masses, from which the trophoblast and embryo arise, as discussed below, are diploid, as are adult stem cells and cancer cells. For Beard’s model of alternating generations in mammals to be correct, either the trophoblast or the embryo would have to be haploid. In fact, all cells in the embryo are diploid for at least the first 3 mo of gestation, and all have arisen by mitosis (11). After the third month, some oogonia arrest their cell division in the prophase of meiosis I; they remain at this stage until puberty, when the first full meiotic cell divisions occur. Beard should not be faulted for this error in his thinking, because nothing was known about DNA or its replication in his time. The alternating sexual and asexual generations’ aspect of Beard’s thinking is not essential to the trophoblast model of cancer.
The Embryo Originates as a Single Cell Produced by the Trophoblast Standard embryology textbooks (11) state that at the 8-cell stage of development the blastomeres undergo compaction and segregate into inner cells and outer cells. At the 16-cell stage (the morula) these cells have formed the inner cell mass and the outer cell mass: The inner cell mass gives rise to the embryo and the outer cell mass gives rise to the trophoblast, which subsequently becomes the placenta. According to standard embryology (11), embryonic stem cells arise from the inner cell mass and are pluripotent; adult stem cells are of unknown origin and are multipotent. Beard (4), on the other hand, believed that the trophoblast appears first and gives rise to a single cell that in turn becomes the embryo. In effect, the trophoblast produces a single spore that becomes the embryo, hence his discussion of alternating sexual and asexual generations in mammals. Beard based this belief on many years of investigation spent examining thousands of slides of embryos from many different species. The simultaneous appearance of the inner and outer cell masses at the 8- and 16-cell stages of development was an accepted fact in embryology in Beard’s time, as it is now, but the theory had never been confirmed by direct observation during Beard’s lifetime. This component of the trophoblast model of cancer—that the trophoblast arises first and gives rise to the embryo—represents a paradigm shift in embryology. If Beard is correct then this testable prediction of his is by itself a significant contribution to biology, independently of the trophoblast model of cancer. Beard’s prediction could be tested by the same histological methods he used and could be tested by reviewing his own slides, if they survived. The alternating generations aspect of Beard’s thinking can be abandoned without his
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essential observation and prediction—that the trophoblast gives rise to the embryo—being imperiled. The trophoblast giving rise to the embryo is an example of the pluripotential, stem cell character of the trophoblast.
Trophoblasts Contain Opposite Stereoisomers of Glucose, Albumin, and Other Molecules Than Do Embryonic Cells Beard (1) stated that trophoblasts, and therefore the placenta, adult stem cells, and cancer cells, contain the opposite stereoisomers of the embryo and the rest of the mature organism, at least for some molecules including glucose and albumin. He was aware of the opinion that only d-glucose occurs in nature but he claimed that Claude Bernard had found l-glucose in the allantois. According to Bernard, Beard said the l-glucose disappears around the fifth or sixth month of human gestation. Beard also thought that l-glucose had been discovered in the mature placenta but he did not cite an author for this claim. Beard hypothesized that trypsin degrades the dalbumin of cancer cells but not the l-albumin of other cells. This is a testable prediction of the trophoblast model of cancer. It could be tested using the techniques of stereochemistry. It is well known that cancer cells consume inordinate amounts of glucose (12), and that they synthesize their own glucose through aerobic glycolysis, which does not occur in normal cells (13). Bicher et al. (14) demonstrated that high levels of l-glucose have a cytotaxic and cytotoxic effect on five different types of cancer cells in vitro, but no effect on normal cells. These observations are as close as the modern literature comes to discussing or testing the stereoisomer component of the trophoblast model of cancer. The author was unable to find any direct evidence for or against the hypothesis in the contemporary literature.
15% of Trophoblast Cells Migrate to Other Tissues in the Body—They Function as Adult Stem Cells Standard embryology texts (11) do not describe ectopic trophoblasts. They state that germ cells, embryonic stem cells, and eventually adult stem cells all arise from the inner cell mass and the embryonic tissue. Beard based his belief that about 15% of trophoblasts migrate to other tissues in the body, where they remain dormant under normal conditions, on his study of thousands of slides of embryos from many different species. This observation predated his development of the trophoblast model of cancer and its treatment by pancreatic enzymes. It is an essential element of the history of Beard’s development of the trophoblast model of cancer that it arose over more than a decade based on a sequence of histological observations. The embryological work that preceded the cancer theory was the basis for Beard’s nomination for the Nobel Prize. Whether or not it is correct, the trophoblast model of cancer is based on observation and scientific reasoning.
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The idea that adult stem cells are ectopic trophoblasts is key to the model because it explains the behavior of trophoblasts that escape normal regulation and become cancerous. This component of the trophoblast model of cancer conflicts with the standard theory of human trophoblasts, which does not mention the possibility of ectopic trophoblasts or link them to adult stem cells: “Trophoblast stem cells (TSC) are defined as pluripotent cells whose differentiated derivatives are restricted to the trophoblast lineages” (15).
Trophoblasts Exhibit the Same Properties As Cancer Cells: Invasive, Undifferentiated, Proliferative, Angiogenic, Resist Immune Surveillance, Reduced Cell Adhesion, Secrete HCG There is no immediately apparent reason why cancer cells should have the properties they do: rapid multiplication, poor differentiation, invasiveness, angiogenesis, resistance to immune surveillance, and resistance to cell adhesion. However, these are the properties of normal trophoblasts during formation of the placenta, as noted by Soundararajan and Rao (16) and Lala, Lee, Xu, and Chakraborty (17). They have to invade the wall of the uterus, create their own blood supply, multiple rapidly, remain undifferentiated, resist cell adhesion, and resist maternal immune surveillance. Trophoblasts are placental stem cells. If any of these trophoblast functions fail, the consequences can be lethal for the embryo. For example, if the trophoblasts could not resist immune surveillance by maternal white blood cells, the evolving placenta would be rejected by a host vs. graft reaction due to the paternal antigens imbedded in the trophoblast cell membranes. Trophoblasts also resemble cancer cells at the biochemical level in terms of their secretory products and cellular markers (18), an example being secretion of human chorionic gonadotrophin (4,19). All of this biology makes sense if ectopic trophoblasts are adult stem cells. When these cells escape their normal dormant state, they start behaving exactly like trophoblast cells do during embryogenesis. They differentiate slightly in the direction of the surrounding tissue because of local signaling in that tissue, but otherwise persist with their mission of invasion and angiogenesis. It follows from the trophoblast model of cancer that cancer research should involve a substantial collaboration with embryology. An approach to cancer treatment is to study the signals that convert the trophoblast into stable, non-malignant, normal placental tissue during normal fetal development. These same signals, introduced into the adult cancer patient, might convert the cancerous trophoblasts back to their stable, dormant state. Lanoix, Lacrasses, Reiter, and Vaillancourt (20), state that, “The trophoblastic cells, with their capacity for proliferation and differentiation, apoptosis and survival, migration, angiogenesis and immune modulation by exploiting similar
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molecular pathways, make them a compelling model for cancer research.” The trophoblast model of cancer states that trophoblasts do not simply provide a useful model for cancer, rather, in the form of ectopic trophoblasts that have escaped normal regulation, they are cancer. This is a testable prediction of the trophoblast model of cancer and can be investigated with the techniques of molecular biology, biochemistry and cell biology, informed by embryology.
Trophoblast That Does Not Get Regulated to Become Stable Placenta Becomes Choriocarcinoma It is stated in standard embryology texts that choriocarcinoma arises from placental tissue (11). This is not disputed. The choriocarcinoma continues to invade the mother until she dies, rather than converting to a stable, normal placenta. According to the trophoblast model of cancer, this is generally true of cancer, except that other cancers arise from ectopic trophoblasts. It follows that choriocarcinoma should provide a model for cancer in general. Understanding the regulatory failures in choriocarcinoma lies within the domains of both embryology and oncology. The trophoblast model of cancer states that this is true for many cancers, not just for choriocarcinoma.
Trophoblast Begins to Transform into Placenta at Day 56 of Human Gestation, at the Same Time as Pancreatic Enzyme Production Begins While studying his slides of embryos in many different species, Beard observed that the trophoblast transforms into the placenta at the same time as pancreatic enzyme production begins in the fetus, which is Day 56 of gestation in humans. The production of trypsin by the fetus in this stage of development has been confirmed in a series of recent studies reviewed by Gonzalez and Isaacs (7).
Pancreatic Enzymes—Trypsin—are the Regulatory Signal that Converts Trophoblast to Placenta Based on his observation that pancreatic enzyme secretion begins on Day 56 of human gestation, Beard hypothesized that trypsin is the regulatory signal that converts the tumor-like trophoblast into stable placenta. Given the complexity of biological systems in general, and placental development in particular (21), it is unlikely that a single regulatory signal controls conversion of the trophoblast into the stable placenta. However, this prediction of the trophoblast model of cancer could be confirmed using the techniques of histology and embryology combined with in vitro studies of the effects of trypsin on trophoblasts. A question to be addressed in such research is the concentration of trypsin in fetal tissues on or about
Day 56 of gestation. Assuming that trypsin does in fact regulate trophoblast conversion to placenta, the threshold for this effect would be relevant to determining the doseresponse curve for the enzyme treatment of cancer and for any possible prophylactic use of enzymes for cancer prevention in humans and in animal models.
Pancreatic Enzymes Can Treat Cancer in the Same Way That They Regulate Transformation of Trophoblast into Placenta In the next step in his thinking, Beard proposed that trypsin might regulate ectopic trophoblasts that have escaped their normal dormant state and become cancer. He paid attention to technical details of the preparation and concentration of enzymes required and stated (1) that many treatment failures during his time were due to inadequate dosage and/or use of inert preparations. Gonzalez (4,5) and Gonzalez and Isaacs (6,7) have also addressed this issue in the current day and have developed a supplier of pancreatic enzymes that meets their criteria. The National Institutes of Health funded a study of the pancreatic enzyme treatment of cancer that yielded negative results (22). The study had a number of serious limitations (5) including insufficient dosage, failure to obtain informed consent, and failure of patients to comply with the treatment protocol. Although it is true that no definitive prospective, randomized, placebo-controlled study of the enzyme treatment of cancer has been conducted, the single cases and case series in the literature (1,6,7) are compelling. Early in the 20th century, again in the 1970s under Dr. Kelley and in the 21st century under the care of Dr. Gonzalez and Dr. Isaacs, dozens of patients with biopsy-confirmed lethal cancers have survived far beyond expectations. This includes multiple patients with biopsy and MRI-confirmed pancreatic cancer who are alive and disease-free after a decade. The cases in Gonzalez (4) and Gonzalez and Isaacs (6,7) are described in great clinical detail and the cancers were diagnosed by independent clinicians working at many different hospitals, including the leading institutions in the country. The results obtained cannot be explained by biased sampling because there is no way to create a biased sample of multiple inoperable pancreatic cancer cases in which survival exceeds 10 yr based on spontaneous remission or favorable prognosis in the absence of treatment. Creating such a biased sample is scientifically impossible. Thus, although the highest level of evidence, a randomized prospective trial, is not available, the existing case reports and case series are more than sufficient to warrant the investment of time, energy and resources in largescale clinical trials. In any such trial, the Gonzalez protocol would need to be followed rigorously with full compliance by patients. Patients who declined participation or who did not comply fully could
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be followed as case controls, as they were in the Gonzalez and Isaacs (6) study of pancreatic cancer patients. The treatment component of the trophoblast model of cancer can be studied with the standard experimental designs of oncology and pharmacology.
Oral Pancreatic Enzyme Supplements Survive Transit Through the Stomach and are Absorbed into the Bloodstream in Active Form Gonzalez and Isaacs (7) have provided evidence that oral pancreatic enzymes survive transit through the stomach and duodenum and are absorbed through the intestinal wall in active form. Any concern that this is not the case has been countered in the literature. Additional research should be conducted on the pharmacokinetics of oral pancreatic enzymes, just as would be done for any other medication or supplement.
Pancreatic Enzymes are Effective for Nausea, Vomiting, and Other Side Effects of Chemotherapy, of the Enzyme Treatment of Cancer, of Preeclampsia and of Other Conditions Beard wrote at length about the separate functions of trypsin and amylase, which he called amylopsin, in his treatment protocol. Amylase, he found, is effective for the side effects of the treatment of cancer with trypsin. He assumed that the side effects were caused by the toxic effects of the breakdown products of cancer cell lysis. He also said that amylase could be used for similar symptoms of nausea and vomiting in a variety of conditions including preeclampsia. Beard thought that the physiology of preeclampsia and the normal regulatory effect of pancreatic enzymes on trophoblasts were likely closely related. This prediction of the trophoblast model of cancer can be tested with a randomized, prospective, placebo-controlled trial. Pancreatic enzymes are widely used as an adjunctive treatment of the side effects of chemotherapy in Europe, based on evidence for their effectiveness in the literature (23). More work is required on which enzymes or combination of enzymes is the most effective for which symptoms.
Additional Components of the Trophoblast Model of Cancer Treatment Protocol The pancreatic enzyme treatment of cancer protocol of Gonzalez and Isaacs (6,7) includes several components that are not core elements of the trophoblast model of cancer. They involve nutritional support of the patient and techniques to reduce side effects, and description of them is included here for completeness.
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Intensive Nutritional Supplementation Assists the Cancer Patient Survive the Enzymatic Treatment of Cancer Both cancer and chemotherapy are toxic to the organism. Symptoms of fatigue, cachexia, nausea, vomiting, hair loss, and neutropenia, among others, are major problems in oncology. The Gonzalez protocol includes a wide range of nutritional supplements designed to support the health and resilience of the cancer patient. The supplements are not anticancer agents as such and are not thought to directly regulate any cancer. They help the person to survive both the cancer and its treatment. In principle, the beneficial effects of the nutritional supplements could be studied in randomized protocols, but any such studies should be delayed until sufficient studies of the complete protocol have been published. This sequence of studies is a standard approach to dissecting the components of a multicomponent treatment protocol for any problem in physical or behavioral medicine. The trophoblast model of cancer states that the active anticancer component is the trypsin, with the other elements being adjunctive and supportive. Nutritional Protocols are Based on Nutritional Types: The 3 Basic Types are Vegetarian (Sympathetic Dominant, Acidic), Balanced, and Meat Eating (Parasympathetic Dominant/Alkaline) In addition to supplements, the Gonzalez protocol includes modifications of diet that are tailored to the patient. Kelley, but not Beard, identified 3 basic nutritional types of person, based on clinical experience and reading of the literature. These are a pure or predominantly vegetarian type, a pure or predominant meat-eating type, and an intermediate, balanced type. The vegetarian type has a sympathetic-dominant autonomic nervous system tone, a more acidic intra- and extracellular environment, and is prone to solid tumors such as breast, colon, liver, lung, ovary, pancreas, and prostate cancer. The meat-eating type, in contrast, has a parasympathetic-dominant autonomic tone, a more basic resting pH, and is prone to immune cell cancers such as Hodgkin’s disease, leukemia, lymphoma, and multiple myeloma. There is epidemiological, preclinical, and clinical evidence that beta-blockers inhibit the progression of at least some types of cancer (24–26). These findings are consistent with the Kelley–Gonzalez hypothesis that a sympathetic-dominant autonomic nervous system could act as a promoter for some forms of cancer. The Kelley diets include (4) a sympathetic-dominant, vegetarian diet of legumes, avocados, cooked root vegetables such as carrots, potatoes, sweet potatoes and yams, and cruciferous vegetables such as broccoli, brussel sprouts, cabbage, and cauliflower, with leafy vegetables and fruits eaten sparingly; a parasympathic-dominant meat diet with 50% of calories from red meat such as lamb, beef, or pork eaten at least once daily plus frequent
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servings of dairy products, and a sparing intake of fish and poultry; and an intermediate, balanced diet. The sympathetic diet is said to be high in beta carotene, thiamin, riboflavin, pyridoxine, biotin, folate, vitamin D, magnesium, chromium, manganese, and potassium, whereas the parasympathetic is comparatively low on these nutrients, but high on vitamins A, B12, and E, pantothenic acid, calcium, phosphorus, iron, selenium, and sodium. These features of the Kelley–Gonzalez nutritional program could be verified by standard nutritional analysis of foods. The concept of nutritional types could be tested through biochemical studies of pH, studies of resting autonomic tone and correlation of these with the preferred precancer diets of patients (vegetarian, meat-eating, or balanced). Resting autonomic tone could potentially be investigated through studies of heart rate variability (27) and perhaps Type A vs. Type B personality (28). Studies of pH could be conducted in vitro with different cell lines with pH varied in both the acidic and basic directions to varying degrees, and with both solid and non-solid tumor lines. This would test the Kelley–Gonzalez hypothesis that different types of cancer survive better in either acidic or basic environments. Parallel studies of pH could be conducted in humans with different types of cancer. No matter what the outcome of such studies and eventual scientific support for or disconfirmation of this component of the treatment model, it is not essential to the trophoblast model of cancer.
Coffee Enemas Stimulate the Liver to More Efficiently Secrete Breakdown Products of Cancer Cell Lysis, Thereby Reducing the Toxicity of Treatment As Gonzalez (4,5) points out, coffee enemas were widely prescribed in conventional medicine throughout the first 3 quarters of the 20th century and were described as conventional treatment in editions of the Merck Manual up until the 1970s. They are not a recent invention and are not derived from alternative or unconventional medicine. Coffee enemas did not disappear from conventional medicine in the last quarter of the 20th century because of disconfirmatory research data or scientific findings. Nevertheless, it is true that coffee enemas are not supported by a body of adequately designed studies. The rationale for coffee enemas is that they stimulate biliary duct peristalsis and discharge of the breakdown products of cancer cell lysis from the liver, thereby reducing the side effects of the enzyme treatment of cancer. There is some evidence (4,5) that coffee enemas do stimulate biliary peristalsis, but further research is required before this can be considered an evidence-based component of the treatment model. This hypothesis could be investigated using standard techniques of physiology including tracer studies and imaging techniques.
DISCUSSION One of the reasons for formulating the predictions of the trophoblast model of cancer as a set of scientifically testable predictions is to establish that it is a scientific model, not simply a set of beliefs or opinions. Another reason is to counter misperceptions about what the model actually predicts, and how the treatment protocol is administered. For example, on the National Cancer Institute website (29) it states that, Supporters of the Gonzalez regimen believe that toxins (harmful substances) in the environment and in processed foods cause cancer to form in the body. These toxins are said to build up in tissues of the body, preventing important body processes from working correctly and letting cancer develop. The theory is that if these toxins could be destroyed and removed from the body, cancer would stop growing. The pancreas secretes enzymes, proteins that help digest food. The Gonzalez regimen is based on the theory that pancreatic enzymes also help the body get rid of toxins that lead to cancer. The coffee enemas are added because they are believed to improve the liver’s ability to remove toxins from the body.
The trophoblast model of cancer is not based on the claim that “toxins” cause cancer, and it is not based on the belief that the treatment protocol counters the effects of oncogenic toxins. The model states, as reviewed above, that the pancreatic enzymes, principally trypsin, cause cancer cell lysis while having no effect on normal cells. The breakdown products of this cell lysis are excreted more efficiently, according to the model, because of the effects of the enzymes and the coffee enemas. The model also states that one or more of the pancreatic enzymes are useful adjuvants for nausea, vomiting, and other symptoms occurring both in a variety of disease states and as a side effect of chemotherapy. Because of the remarkable survival times—over a decade in many biopsy and MRI-confirmed inoperable pancreatic cancers—described by Beard and Gonzalez and Isaacs, because the treatment protocol is based on the work of a Nobel Prizenominated embryologist, because the trophoblast model of cancer is a detailed, scientifically testable model, and because it leads to a specific avenue of investigation into cancer, it should be investigated and tested by a wide range of different scientists and clinicians including oncologists, embryologists, physiologists, and molecular biologists. If this model is correct and applies to even a subset of cancers, it is a noteworthy contribution to the field (30,31). The trophoblast model of cancer is consistent with our current understanding adult stem cells (32): It adds to current models the hypothesis that at least a subset of adult stem cells are ectopic trophoblasts. Finally, the trophoblast model of cancer is worthy of further study because it is supported by preliminary animal data (33). In this study, malignant human pancreatic cell line AsPCI was transplanted into the pancreases of mice in 2 experiments: In 1, the survival rate of mice at Day 35 was 79% in the mice treated with pancreatic enzymes and 29% in the control mice; in the second experiment, survival at Day 49 was 64% in the
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mice treated with pancreatic enzymes and 29% in the control group. In the mouse study, the same enzyme preparation was used as in the clinical treatment of humans by Gonzalez and Isaacs (6), in which survival time for pancreatic cancer patients was 81% at 1 yr, 45% at 2 yr, and 36% at 3 yr, compared to survival rates of 25% at 1 yr and 10% at 2 yr for all pancreatic cancers combined in the National Cancer Database.
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REFERENCES 1. Beard J: The Enzyme Treatment of Cancer and its Scientific Basis. New York, NY: New Spring Press, 2010. (Original work published in 1911). 2. Moss RW: Enzymes, trophoblasts, and cancer: The afterlife of an idea (1924–2008). Integr Cancer Ther 7, 262–275, 2008. 3. Moss RW: The life and times of John Beard, DSc (1858–1924). Integr Cancer Ther 7, 229–251, 2008. 4. Gonzalez NJ: One Man Alone. An Investigation of Nutrition, Cancer and William Donald Kelley. New York, NY: New Spring Press, 2010. 5. Gonzalez NJ: What Went Wrong? The Truth Behind the Clinical Trial of the Enzyme Treatment of Cancer. New York, NY: New Spring Press, 2012. 6. Gonzalez NJ and Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nut Cancer 33, 117–124, 1999. 7. Gonzalez NJ and Isaacs LL: The Trophoblast and the Origins of Cancer. One Solution to the Medical Enigma of Our Time. New York, NY: New Spring Press, 2009. 8. Bischof P and Irminger-Finger I: The human cytotrophoblastic cell, a mononuclear chameleon. Int J Biochem Cell Biol 37, 1–16, 2008. 9. King M-C, Marks JH, and Mandell, JB: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643– 646, 2003. 10. Neves RC, Cunha MR, Funch P, Surowiec I, Mitagvaria N, et al.: Comparative myoanatomy of cycliophoran life cycle stages. J Morphol 271, 596–611, 2010. 11. Sadler TW: Medical Embryology, 12th ed. New York, NY: Wolters Kluwer/Lippincott Williams & Wilkin, 2012. 12. Graham NA, Tahmasian M, Kohli B, Komisopoulou, E, Zhu, M, et al.: Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol 8, 589, 2012. doi:10.1038/ msb.2012.20 13. Kellenberger LD, Bruin JE, Greenaway J, Campbell NE, Moorehead RA, et al.: The role of dysregulated glucose metabolism in epithelial ovarian cancer. J Oncol, 2010. doi:10.1155/2010/514310 14. Bicher HI, Yarmoninko S, Wainson A, Surowiec I, and Mitagvaria N: Anticancer effect of l-glucose on vivo-potentiation of hyperthermia. South Med J 88, S141, 1995.
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15. Douglas CG, VandeVoort CA, Kumar P, Chang T-C, and Golos TG: Trophoblast stem cells: Models for investigating trophectoderm differentiation and placental development. Endocr Rev 30, 228–240, 2009. 16. Soundararajan R and Rao AJ: Trophoblast ‘pseudo-tumorigenesis’: significance and contributory factors. Reprod Biol Endocrinol 2, 15–22, 2004. 17. Lala PK, Lee BP, Xu G, and Chakraborty C: Human placental trophoblast as an in vitro model for tumor progression. Can J Physiol Pharmacol 80, 142–149, 2002. 18. Cohen M and Bischof P: Factors regulating trophoblast invasion. Gynecol Obstet Invest 64, 126–130, 2007. 19. Acevedo H, Harstock RJ, and Maroon JC: Detection of membrane-associated human chorionic gonadotrophin and its subunits on human cultured cancer cells of the nervous system. Cancer Detect Prev 21, 295–303, 1997. 20. Lanoix D, Lacrasses AA, and Reiter RJ: Melatonin: the smart killer: the human trophoblast as a model. Mol Cellul Endocrinol 348, 1–11, 2012. 21. Power ML and Schulkin J: The Evolution of the Human Placenta. Baltimore, MD: Johns Hopkins University Press, 2012. 22. Chabot JA, Tsai WY, Fine RL, Chen C, Kumah CK, et al.: Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol 28, 2058–2063, 2010. 23. Block KI: Enzymes and cancer: A look toward the past as we move forward. Integr Cancer Ther 7, 223–225, 2008. 24. Barron TI, Sharp L, and Visvanathan K: Beta-adrenergic blocking drugs in breast cancer: a perspective review. Ther Adv Med Oncol 4, 113–125, 2012. 25. Cole S and Sood AK: Molecular pathways: Beta-adrenergic signaling in cancer. Clin Cancer Res 18, 1201–1206, 2011. 26. Ji Y, Chen S, Xiao X, and Li K: Zhen Beta-blockers: a novel class of antitumor agents. Onco Target Ther 5, 391–401, 2012. 27. Xhyheri B, Manfrini O, Mazzolini M, Pizzi C, and Bugiardini R: Heart rate variability today. Prog Cardiovasc Dis 55, 321–331, 2012. 28. Ng JH, Lo S, Lim F, Goh S, and Kanagalingam J: Association between anxiety, type A personality, and treatment outcome of dysphonia due to benign causes. Otolaryngol Head Neck Surg 148, 96–102, 2013. 29. Ross, CA: Questions and answers about the Gonzalez regimen. Retrieved from www.cancer.gov/cancertopics/pdq/cam/gonzalez/Patient/page2 30. Beuth J: Proteolytic enzyme therapy in evidence-based complementary medicine. Integr Cancer Ther 7, 311–316, 2008. 31. Burleigh AR: Of germ cells, trophoblasts and cancer stem cells. Integr Cancer Ther 7, 276–228, 200832. 32. Van de Stolpe A: On the origin and destination of cancer cells: a conceptual evaluation. Am J Cancer Res 3, 107–116, 2013. 33. Saruc R, Standop S, Nozawa F, Itami A, Pandey KK, et al.: Pancreatic enzyme extract improves survival in murine pancreatic cancer. Pancreas 28, 401–412, 2004.
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The Trophoblast Model of Cancer a
Colin A. Ross a
The Colin A. Ross Institute for Psychological Trauma, Richardson, Texas, USA Published online: 05 Nov 2014.
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Nutrition and Cancer, 0(0), 1–7 Copyright Ó 2014, Taylor & Francis Group, LLC ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.956257
The Trophoblast Model of Cancer Colin A. Ross
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The Colin A. Ross Institute for Psychological Trauma, Richardson, Texas, USA
John Beard, the British embryologist and histologist, first proposed his trophoblast model of cancer in 1902. The model has subsequently been expanded by Kelley, and in current times, Gonzalez and Isaacs. The trophoblast model of cancer can be stated as a specified, scientifically testable model, including its core predictions that 1) adult stem cells are ectopic trophoblasts that have migrated to other tissues early in embryogenesis; 2) pancreatic enzymes are the key signal that converts the trophoblast into the stable placenta; 3) cancer arises from trophoblasts that have escaped regulatory control; and 4) pancreatic enzymes can be used to treat cancer. The author reviewed the literature on the trophoblast model of cancer and the use of pancreatic enzymes for the treatment of cancer and organized its key tenets into a set of specified scientific hypotheses. The trophoblast model of cancer can be stated as a set of 11 core predictions and 3 adjunctive or nonessential components. The trophoblast model of cancer is a detailed, testable model that should be investigated within an overlapping set of fields including oncology, histology, physiology, molecular biology, and embryology.
INTRODUCTION The trophoblast model of cancer originally developed by Beard (1), and refined by Kelley (2,3), Gonzalez (4,5), and Gonzalez and Isaacs (6,7), is a scientifically testable model. Beard was nominated for a Nobel Prize because of the quality and originality of his work in embryology. He was the first to identify adult stem cells. He was also the first person to propose that the corpus luteum inhibits ovulation during pregnancy, the first to describe the immunological functions of the thymus, and the first to describe cell apoptosis based on his histological studies of fish embryos. He also co-discovered the Rohon-Beard cells in the spinal cord (3). Beard (1) noticed that the transformation from trophoblast to stable placenta occurs at the same time as the pancreas appears in fetal development and begins to secrete enzymes. He therefore hypothesized that these enzymes, principally trypsin, are the Submitted 2 December 2013; accepted in final form 16 August 2014. Address correspondence to Colin A. Ross, The Colin A. Ross Institute for Psychological Trauma, 1701 Gateway #349, Richardson, TX 75080. Phone: 972-918-9599. E-mail: [email protected]
regulatory signal that controls this transformation. When this regulatory process fails, a choriocarcinoma develops. Another key observation of Beard’s was the existence of what he called wayward trophoblasts. He observed that about 15% of trophoblast cells are distributed throughout the body, where they reside in dormant form in different tissues and organs. In contemporary terminology, these ectopic trophoblasts are adult stem cells. Cancer occurs when, for unknown reasons, these adult stem cells escape normal regulatory control and begin to behave like normal trophoblasts do when they are forming the placenta: They invade, multiply, create their own blood supply, resist immune surveillance, resist cell adhesion, and remain undifferentiated compared to adult tissue and compared to the mature placenta. According to the trophoblast model, cancer cells are not dedifferentiated normal cells. Rather, they are normal trophoblasts that have escaped regulatory control and that take on some characteristics of the local tissue due to local signaling in the tissue. Thus, liver cancer cells look like dedifferentiated liver cells but are actually normal trophoblasts that have partially differentiated in the direction of liver cells. It follows from the model that the targets of cancer treatment should be a small population of dysregulated adult stem cells within normal tissue. The ability of trophoblasts to differentiate in the direction of neighboring normal tissue is well described by Bischof and Irminger-Finger (8): “Like a chameleon, CTB [cytotrophoblastic cells] are thus able to adapt to their immediate environment by phenocopying their neighbor cells.” The final step in Beard’s development of the trophoblast model of cancer was his prediction that trypsin could be an effective treatment for cancer because it would have the same effect on cancer cells as it does on embryonic trophoblast; it would cause the cells to differentiate, stop multiplying, stop being angiogenic, stop invading, and demonstrate normal cell adhesion. Whether or not the model is correct, it can be formulated as a specified, scientifically testable theory: Providing that formulation is the purpose of the present article. It is possible that some or many tenets of the model could be incorrect, whereas the treatment of cancer with pancreatic enzymes is effective for unknown reasons. 1
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The trophoblast model of cancer and models based on genetically driven dedifferentiation of normal cells are not mutually exclusive, even though Beard hypothesized that his model applies to all cancers. Given the complexity of biological systems and cancer, it seems unlikely that any one theory or approach could account for all cases. Even if correct, the trophoblast model does not specify all the regulatory signals and mechanisms involved and, most importantly, it is silent on the triggers that stimulate the escape of adult stem cells from normal regulatory control. These would presumably include known genetic and environmental risk factors for cancer. For example, perhaps the normal versions of the BRCA1 and BRCA2 genes (9) function to keep adult stem cells in the breast and uterus in a dormant state: the abnormal variants of the genes fail to perform this function and thereby allow the stem cells to escape control. BRCA mutations as risk factors are equally compatible with the trophoblast and normal cell dedifferentiation models of cancer.
CORE COMPONENTS OF THE TROPHOBLAST MODEL OF CANCER The core components of the trophoblast model of cancer as developed by Beard (1) and refined by Kelley (2,3), Gonzalez and Isaacs (6,7) follow.
THE SEXUAL–ASEXUAL ALTERNATION OF GENERATIONS IN PLANTS ALSO OCCURS IN MAMMALS Beard thought that the sexual–asexual alternation of generations in plants also occurs in mammals. It is an accepted fact in biology that plants and some lower animal species such as cycliophora, which lives in the mouths of lobsters, exhibit an alternation of generations (10). Generations, in this usage of the term, means that there are alternating multicellular haploid and diploid forms of a given species, such as cycliophora. In plants, the haploid or sexual generation is the gametophyte, whereas the diploid or asexual generation is the sporophyte. In animals, there is an alternation of generations in the sense that the diploid adult alternates with the haploid egg or sperm, but this is not an alternation of generations in the above sense because the haploid stage is unicellular. From an evolutionary perspective, the alternation of generations is conserved, but in higher life forms the haploid generation is unicellular. Considering this similarity between flowering plants and animals, it seems reasonable to say that there is an alternation of generations in mammals, as Beard thought, as long as one does not require a multicellular gametophyte. Beard wrote before DNA was discovered and before the terms haploid, diploid, meiosis, and mitosis had entered the literature. He believed, based on his careful histological observations, that the trophoblast gives rise to the embryo, which then matures to become the adult. In effect, the trophoblast
produces a single-cell spore early in development that becomes the embryo. Beard thought that the alternation of generations in mammals was exactly the same as in plants. This cannot be true because both the inner and outer cell masses, from which the trophoblast and embryo arise, as discussed below, are diploid, as are adult stem cells and cancer cells. For Beard’s model of alternating generations in mammals to be correct, either the trophoblast or the embryo would have to be haploid. In fact, all cells in the embryo are diploid for at least the first 3 mo of gestation, and all have arisen by mitosis (11). After the third month, some oogonia arrest their cell division in the prophase of meiosis I; they remain at this stage until puberty, when the first full meiotic cell divisions occur. Beard should not be faulted for this error in his thinking, because nothing was known about DNA or its replication in his time. The alternating sexual and asexual generations’ aspect of Beard’s thinking is not essential to the trophoblast model of cancer.
The Embryo Originates as a Single Cell Produced by the Trophoblast Standard embryology textbooks (11) state that at the 8-cell stage of development the blastomeres undergo compaction and segregate into inner cells and outer cells. At the 16-cell stage (the morula) these cells have formed the inner cell mass and the outer cell mass: The inner cell mass gives rise to the embryo and the outer cell mass gives rise to the trophoblast, which subsequently becomes the placenta. According to standard embryology (11), embryonic stem cells arise from the inner cell mass and are pluripotent; adult stem cells are of unknown origin and are multipotent. Beard (4), on the other hand, believed that the trophoblast appears first and gives rise to a single cell that in turn becomes the embryo. In effect, the trophoblast produces a single spore that becomes the embryo, hence his discussion of alternating sexual and asexual generations in mammals. Beard based this belief on many years of investigation spent examining thousands of slides of embryos from many different species. The simultaneous appearance of the inner and outer cell masses at the 8- and 16-cell stages of development was an accepted fact in embryology in Beard’s time, as it is now, but the theory had never been confirmed by direct observation during Beard’s lifetime. This component of the trophoblast model of cancer—that the trophoblast arises first and gives rise to the embryo—represents a paradigm shift in embryology. If Beard is correct then this testable prediction of his is by itself a significant contribution to biology, independently of the trophoblast model of cancer. Beard’s prediction could be tested by the same histological methods he used and could be tested by reviewing his own slides, if they survived. The alternating generations aspect of Beard’s thinking can be abandoned without his
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essential observation and prediction—that the trophoblast gives rise to the embryo—being imperiled. The trophoblast giving rise to the embryo is an example of the pluripotential, stem cell character of the trophoblast.
Trophoblasts Contain Opposite Stereoisomers of Glucose, Albumin, and Other Molecules Than Do Embryonic Cells Beard (1) stated that trophoblasts, and therefore the placenta, adult stem cells, and cancer cells, contain the opposite stereoisomers of the embryo and the rest of the mature organism, at least for some molecules including glucose and albumin. He was aware of the opinion that only d-glucose occurs in nature but he claimed that Claude Bernard had found l-glucose in the allantois. According to Bernard, Beard said the l-glucose disappears around the fifth or sixth month of human gestation. Beard also thought that l-glucose had been discovered in the mature placenta but he did not cite an author for this claim. Beard hypothesized that trypsin degrades the dalbumin of cancer cells but not the l-albumin of other cells. This is a testable prediction of the trophoblast model of cancer. It could be tested using the techniques of stereochemistry. It is well known that cancer cells consume inordinate amounts of glucose (12), and that they synthesize their own glucose through aerobic glycolysis, which does not occur in normal cells (13). Bicher et al. (14) demonstrated that high levels of l-glucose have a cytotaxic and cytotoxic effect on five different types of cancer cells in vitro, but no effect on normal cells. These observations are as close as the modern literature comes to discussing or testing the stereoisomer component of the trophoblast model of cancer. The author was unable to find any direct evidence for or against the hypothesis in the contemporary literature.
15% of Trophoblast Cells Migrate to Other Tissues in the Body—They Function as Adult Stem Cells Standard embryology texts (11) do not describe ectopic trophoblasts. They state that germ cells, embryonic stem cells, and eventually adult stem cells all arise from the inner cell mass and the embryonic tissue. Beard based his belief that about 15% of trophoblasts migrate to other tissues in the body, where they remain dormant under normal conditions, on his study of thousands of slides of embryos from many different species. This observation predated his development of the trophoblast model of cancer and its treatment by pancreatic enzymes. It is an essential element of the history of Beard’s development of the trophoblast model of cancer that it arose over more than a decade based on a sequence of histological observations. The embryological work that preceded the cancer theory was the basis for Beard’s nomination for the Nobel Prize. Whether or not it is correct, the trophoblast model of cancer is based on observation and scientific reasoning.
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The idea that adult stem cells are ectopic trophoblasts is key to the model because it explains the behavior of trophoblasts that escape normal regulation and become cancerous. This component of the trophoblast model of cancer conflicts with the standard theory of human trophoblasts, which does not mention the possibility of ectopic trophoblasts or link them to adult stem cells: “Trophoblast stem cells (TSC) are defined as pluripotent cells whose differentiated derivatives are restricted to the trophoblast lineages” (15).
Trophoblasts Exhibit the Same Properties As Cancer Cells: Invasive, Undifferentiated, Proliferative, Angiogenic, Resist Immune Surveillance, Reduced Cell Adhesion, Secrete HCG There is no immediately apparent reason why cancer cells should have the properties they do: rapid multiplication, poor differentiation, invasiveness, angiogenesis, resistance to immune surveillance, and resistance to cell adhesion. However, these are the properties of normal trophoblasts during formation of the placenta, as noted by Soundararajan and Rao (16) and Lala, Lee, Xu, and Chakraborty (17). They have to invade the wall of the uterus, create their own blood supply, multiple rapidly, remain undifferentiated, resist cell adhesion, and resist maternal immune surveillance. Trophoblasts are placental stem cells. If any of these trophoblast functions fail, the consequences can be lethal for the embryo. For example, if the trophoblasts could not resist immune surveillance by maternal white blood cells, the evolving placenta would be rejected by a host vs. graft reaction due to the paternal antigens imbedded in the trophoblast cell membranes. Trophoblasts also resemble cancer cells at the biochemical level in terms of their secretory products and cellular markers (18), an example being secretion of human chorionic gonadotrophin (4,19). All of this biology makes sense if ectopic trophoblasts are adult stem cells. When these cells escape their normal dormant state, they start behaving exactly like trophoblast cells do during embryogenesis. They differentiate slightly in the direction of the surrounding tissue because of local signaling in that tissue, but otherwise persist with their mission of invasion and angiogenesis. It follows from the trophoblast model of cancer that cancer research should involve a substantial collaboration with embryology. An approach to cancer treatment is to study the signals that convert the trophoblast into stable, non-malignant, normal placental tissue during normal fetal development. These same signals, introduced into the adult cancer patient, might convert the cancerous trophoblasts back to their stable, dormant state. Lanoix, Lacrasses, Reiter, and Vaillancourt (20), state that, “The trophoblastic cells, with their capacity for proliferation and differentiation, apoptosis and survival, migration, angiogenesis and immune modulation by exploiting similar
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molecular pathways, make them a compelling model for cancer research.” The trophoblast model of cancer states that trophoblasts do not simply provide a useful model for cancer, rather, in the form of ectopic trophoblasts that have escaped normal regulation, they are cancer. This is a testable prediction of the trophoblast model of cancer and can be investigated with the techniques of molecular biology, biochemistry and cell biology, informed by embryology.
Trophoblast That Does Not Get Regulated to Become Stable Placenta Becomes Choriocarcinoma It is stated in standard embryology texts that choriocarcinoma arises from placental tissue (11). This is not disputed. The choriocarcinoma continues to invade the mother until she dies, rather than converting to a stable, normal placenta. According to the trophoblast model of cancer, this is generally true of cancer, except that other cancers arise from ectopic trophoblasts. It follows that choriocarcinoma should provide a model for cancer in general. Understanding the regulatory failures in choriocarcinoma lies within the domains of both embryology and oncology. The trophoblast model of cancer states that this is true for many cancers, not just for choriocarcinoma.
Trophoblast Begins to Transform into Placenta at Day 56 of Human Gestation, at the Same Time as Pancreatic Enzyme Production Begins While studying his slides of embryos in many different species, Beard observed that the trophoblast transforms into the placenta at the same time as pancreatic enzyme production begins in the fetus, which is Day 56 of gestation in humans. The production of trypsin by the fetus in this stage of development has been confirmed in a series of recent studies reviewed by Gonzalez and Isaacs (7).
Pancreatic Enzymes—Trypsin—are the Regulatory Signal that Converts Trophoblast to Placenta Based on his observation that pancreatic enzyme secretion begins on Day 56 of human gestation, Beard hypothesized that trypsin is the regulatory signal that converts the tumor-like trophoblast into stable placenta. Given the complexity of biological systems in general, and placental development in particular (21), it is unlikely that a single regulatory signal controls conversion of the trophoblast into the stable placenta. However, this prediction of the trophoblast model of cancer could be confirmed using the techniques of histology and embryology combined with in vitro studies of the effects of trypsin on trophoblasts. A question to be addressed in such research is the concentration of trypsin in fetal tissues on or about
Day 56 of gestation. Assuming that trypsin does in fact regulate trophoblast conversion to placenta, the threshold for this effect would be relevant to determining the doseresponse curve for the enzyme treatment of cancer and for any possible prophylactic use of enzymes for cancer prevention in humans and in animal models.
Pancreatic Enzymes Can Treat Cancer in the Same Way That They Regulate Transformation of Trophoblast into Placenta In the next step in his thinking, Beard proposed that trypsin might regulate ectopic trophoblasts that have escaped their normal dormant state and become cancer. He paid attention to technical details of the preparation and concentration of enzymes required and stated (1) that many treatment failures during his time were due to inadequate dosage and/or use of inert preparations. Gonzalez (4,5) and Gonzalez and Isaacs (6,7) have also addressed this issue in the current day and have developed a supplier of pancreatic enzymes that meets their criteria. The National Institutes of Health funded a study of the pancreatic enzyme treatment of cancer that yielded negative results (22). The study had a number of serious limitations (5) including insufficient dosage, failure to obtain informed consent, and failure of patients to comply with the treatment protocol. Although it is true that no definitive prospective, randomized, placebo-controlled study of the enzyme treatment of cancer has been conducted, the single cases and case series in the literature (1,6,7) are compelling. Early in the 20th century, again in the 1970s under Dr. Kelley and in the 21st century under the care of Dr. Gonzalez and Dr. Isaacs, dozens of patients with biopsy-confirmed lethal cancers have survived far beyond expectations. This includes multiple patients with biopsy and MRI-confirmed pancreatic cancer who are alive and disease-free after a decade. The cases in Gonzalez (4) and Gonzalez and Isaacs (6,7) are described in great clinical detail and the cancers were diagnosed by independent clinicians working at many different hospitals, including the leading institutions in the country. The results obtained cannot be explained by biased sampling because there is no way to create a biased sample of multiple inoperable pancreatic cancer cases in which survival exceeds 10 yr based on spontaneous remission or favorable prognosis in the absence of treatment. Creating such a biased sample is scientifically impossible. Thus, although the highest level of evidence, a randomized prospective trial, is not available, the existing case reports and case series are more than sufficient to warrant the investment of time, energy and resources in largescale clinical trials. In any such trial, the Gonzalez protocol would need to be followed rigorously with full compliance by patients. Patients who declined participation or who did not comply fully could
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be followed as case controls, as they were in the Gonzalez and Isaacs (6) study of pancreatic cancer patients. The treatment component of the trophoblast model of cancer can be studied with the standard experimental designs of oncology and pharmacology.
Oral Pancreatic Enzyme Supplements Survive Transit Through the Stomach and are Absorbed into the Bloodstream in Active Form Gonzalez and Isaacs (7) have provided evidence that oral pancreatic enzymes survive transit through the stomach and duodenum and are absorbed through the intestinal wall in active form. Any concern that this is not the case has been countered in the literature. Additional research should be conducted on the pharmacokinetics of oral pancreatic enzymes, just as would be done for any other medication or supplement.
Pancreatic Enzymes are Effective for Nausea, Vomiting, and Other Side Effects of Chemotherapy, of the Enzyme Treatment of Cancer, of Preeclampsia and of Other Conditions Beard wrote at length about the separate functions of trypsin and amylase, which he called amylopsin, in his treatment protocol. Amylase, he found, is effective for the side effects of the treatment of cancer with trypsin. He assumed that the side effects were caused by the toxic effects of the breakdown products of cancer cell lysis. He also said that amylase could be used for similar symptoms of nausea and vomiting in a variety of conditions including preeclampsia. Beard thought that the physiology of preeclampsia and the normal regulatory effect of pancreatic enzymes on trophoblasts were likely closely related. This prediction of the trophoblast model of cancer can be tested with a randomized, prospective, placebo-controlled trial. Pancreatic enzymes are widely used as an adjunctive treatment of the side effects of chemotherapy in Europe, based on evidence for their effectiveness in the literature (23). More work is required on which enzymes or combination of enzymes is the most effective for which symptoms.
Additional Components of the Trophoblast Model of Cancer Treatment Protocol The pancreatic enzyme treatment of cancer protocol of Gonzalez and Isaacs (6,7) includes several components that are not core elements of the trophoblast model of cancer. They involve nutritional support of the patient and techniques to reduce side effects, and description of them is included here for completeness.
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Intensive Nutritional Supplementation Assists the Cancer Patient Survive the Enzymatic Treatment of Cancer Both cancer and chemotherapy are toxic to the organism. Symptoms of fatigue, cachexia, nausea, vomiting, hair loss, and neutropenia, among others, are major problems in oncology. The Gonzalez protocol includes a wide range of nutritional supplements designed to support the health and resilience of the cancer patient. The supplements are not anticancer agents as such and are not thought to directly regulate any cancer. They help the person to survive both the cancer and its treatment. In principle, the beneficial effects of the nutritional supplements could be studied in randomized protocols, but any such studies should be delayed until sufficient studies of the complete protocol have been published. This sequence of studies is a standard approach to dissecting the components of a multicomponent treatment protocol for any problem in physical or behavioral medicine. The trophoblast model of cancer states that the active anticancer component is the trypsin, with the other elements being adjunctive and supportive. Nutritional Protocols are Based on Nutritional Types: The 3 Basic Types are Vegetarian (Sympathetic Dominant, Acidic), Balanced, and Meat Eating (Parasympathetic Dominant/Alkaline) In addition to supplements, the Gonzalez protocol includes modifications of diet that are tailored to the patient. Kelley, but not Beard, identified 3 basic nutritional types of person, based on clinical experience and reading of the literature. These are a pure or predominantly vegetarian type, a pure or predominant meat-eating type, and an intermediate, balanced type. The vegetarian type has a sympathetic-dominant autonomic nervous system tone, a more acidic intra- and extracellular environment, and is prone to solid tumors such as breast, colon, liver, lung, ovary, pancreas, and prostate cancer. The meat-eating type, in contrast, has a parasympathetic-dominant autonomic tone, a more basic resting pH, and is prone to immune cell cancers such as Hodgkin’s disease, leukemia, lymphoma, and multiple myeloma. There is epidemiological, preclinical, and clinical evidence that beta-blockers inhibit the progression of at least some types of cancer (24–26). These findings are consistent with the Kelley–Gonzalez hypothesis that a sympathetic-dominant autonomic nervous system could act as a promoter for some forms of cancer. The Kelley diets include (4) a sympathetic-dominant, vegetarian diet of legumes, avocados, cooked root vegetables such as carrots, potatoes, sweet potatoes and yams, and cruciferous vegetables such as broccoli, brussel sprouts, cabbage, and cauliflower, with leafy vegetables and fruits eaten sparingly; a parasympathic-dominant meat diet with 50% of calories from red meat such as lamb, beef, or pork eaten at least once daily plus frequent
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servings of dairy products, and a sparing intake of fish and poultry; and an intermediate, balanced diet. The sympathetic diet is said to be high in beta carotene, thiamin, riboflavin, pyridoxine, biotin, folate, vitamin D, magnesium, chromium, manganese, and potassium, whereas the parasympathetic is comparatively low on these nutrients, but high on vitamins A, B12, and E, pantothenic acid, calcium, phosphorus, iron, selenium, and sodium. These features of the Kelley–Gonzalez nutritional program could be verified by standard nutritional analysis of foods. The concept of nutritional types could be tested through biochemical studies of pH, studies of resting autonomic tone and correlation of these with the preferred precancer diets of patients (vegetarian, meat-eating, or balanced). Resting autonomic tone could potentially be investigated through studies of heart rate variability (27) and perhaps Type A vs. Type B personality (28). Studies of pH could be conducted in vitro with different cell lines with pH varied in both the acidic and basic directions to varying degrees, and with both solid and non-solid tumor lines. This would test the Kelley–Gonzalez hypothesis that different types of cancer survive better in either acidic or basic environments. Parallel studies of pH could be conducted in humans with different types of cancer. No matter what the outcome of such studies and eventual scientific support for or disconfirmation of this component of the treatment model, it is not essential to the trophoblast model of cancer.
Coffee Enemas Stimulate the Liver to More Efficiently Secrete Breakdown Products of Cancer Cell Lysis, Thereby Reducing the Toxicity of Treatment As Gonzalez (4,5) points out, coffee enemas were widely prescribed in conventional medicine throughout the first 3 quarters of the 20th century and were described as conventional treatment in editions of the Merck Manual up until the 1970s. They are not a recent invention and are not derived from alternative or unconventional medicine. Coffee enemas did not disappear from conventional medicine in the last quarter of the 20th century because of disconfirmatory research data or scientific findings. Nevertheless, it is true that coffee enemas are not supported by a body of adequately designed studies. The rationale for coffee enemas is that they stimulate biliary duct peristalsis and discharge of the breakdown products of cancer cell lysis from the liver, thereby reducing the side effects of the enzyme treatment of cancer. There is some evidence (4,5) that coffee enemas do stimulate biliary peristalsis, but further research is required before this can be considered an evidence-based component of the treatment model. This hypothesis could be investigated using standard techniques of physiology including tracer studies and imaging techniques.
DISCUSSION One of the reasons for formulating the predictions of the trophoblast model of cancer as a set of scientifically testable predictions is to establish that it is a scientific model, not simply a set of beliefs or opinions. Another reason is to counter misperceptions about what the model actually predicts, and how the treatment protocol is administered. For example, on the National Cancer Institute website (29) it states that, Supporters of the Gonzalez regimen believe that toxins (harmful substances) in the environment and in processed foods cause cancer to form in the body. These toxins are said to build up in tissues of the body, preventing important body processes from working correctly and letting cancer develop. The theory is that if these toxins could be destroyed and removed from the body, cancer would stop growing. The pancreas secretes enzymes, proteins that help digest food. The Gonzalez regimen is based on the theory that pancreatic enzymes also help the body get rid of toxins that lead to cancer. The coffee enemas are added because they are believed to improve the liver’s ability to remove toxins from the body.
The trophoblast model of cancer is not based on the claim that “toxins” cause cancer, and it is not based on the belief that the treatment protocol counters the effects of oncogenic toxins. The model states, as reviewed above, that the pancreatic enzymes, principally trypsin, cause cancer cell lysis while having no effect on normal cells. The breakdown products of this cell lysis are excreted more efficiently, according to the model, because of the effects of the enzymes and the coffee enemas. The model also states that one or more of the pancreatic enzymes are useful adjuvants for nausea, vomiting, and other symptoms occurring both in a variety of disease states and as a side effect of chemotherapy. Because of the remarkable survival times—over a decade in many biopsy and MRI-confirmed inoperable pancreatic cancers—described by Beard and Gonzalez and Isaacs, because the treatment protocol is based on the work of a Nobel Prizenominated embryologist, because the trophoblast model of cancer is a detailed, scientifically testable model, and because it leads to a specific avenue of investigation into cancer, it should be investigated and tested by a wide range of different scientists and clinicians including oncologists, embryologists, physiologists, and molecular biologists. If this model is correct and applies to even a subset of cancers, it is a noteworthy contribution to the field (30,31). The trophoblast model of cancer is consistent with our current understanding adult stem cells (32): It adds to current models the hypothesis that at least a subset of adult stem cells are ectopic trophoblasts. Finally, the trophoblast model of cancer is worthy of further study because it is supported by preliminary animal data (33). In this study, malignant human pancreatic cell line AsPCI was transplanted into the pancreases of mice in 2 experiments: In 1, the survival rate of mice at Day 35 was 79% in the mice treated with pancreatic enzymes and 29% in the control mice; in the second experiment, survival at Day 49 was 64% in the
THE TROPHOBLAST MODEL OF CANCER
mice treated with pancreatic enzymes and 29% in the control group. In the mouse study, the same enzyme preparation was used as in the clinical treatment of humans by Gonzalez and Isaacs (6), in which survival time for pancreatic cancer patients was 81% at 1 yr, 45% at 2 yr, and 36% at 3 yr, compared to survival rates of 25% at 1 yr and 10% at 2 yr for all pancreatic cancers combined in the National Cancer Database.
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