"The doctor of the future will give no medicine, but will interest his patients in the care of the human frame, in diet and in the cause and prevention of disease."
- Thomas Edison
Bone marrow stem cells cause stomach cancer.
The rare childhood cancer called retinoblastoma exhibit various markers and
behaviors more characteristic of cells from an embryo. For example, these
cells form tiny 'microspheres,' just as typical stem cells do. "Generally
speaking, it is only the
cancer stem cell
that perpetuates itself indefinitely and is capable of forming new tumors or
Feverfew vs. Malignant Stem Cells
Learn more about
trophoblast cells and cancer.
enzymes and cancer.
Ralph W. Moss, Ph.D. Weekly CancerDecisions.com
Newsletter #81 04/26/03
Scientists Identify Stem Cells As Hidden Cause of Cancer
© 2003 by Ralph W. Moss, PhD
Earlier this month, University of Michigan (U-M) scientists revealed that a malignant form of stem cells may be responsible for the development of breast cancer. According to a U-M press release, this new understanding is "a paradigm shift in cancer research," and the University has promised to raise $12 million to further explore this concept.
The Ann Arbor researchers discovered that not all cells in a tumor are equally malignant. Only a tiny minority of tumor cells are actually capable of inducing new cancers; the rest are relatively harmless. "These tumor-inducing cells have many of the properties of stem cells," said Michael F. Clarke, MD, a professor of internal medicine, who directed the study. "They make copies of themselves --a process called self-renewal --and produce all the other kinds of cells in the original tumor."
The University of Michigan team isolated the tumor-inducing cells from breast cancers, both primary and metastatic, which had been removed from nine women who were treated at the University's Comprehensive Cancer Center. Similar cancer-causing stem cells have previously been identified in leukemia (cancer of the blood), but these are the first such cancer stem cells to be found in solid tumors.
The discovery was first announced in February in the online edition of the Proceedings of the National Academy of Sciences (PNAS) and has now been published in the print version of that prestigious journal. The existence of this highly malignant subset of cells may explain why current treatments for metastatic breast cancer often fail, according to Max S. Wicha, MD, an oncologist and director of the University of Michigan Comprehensive Cancer Center, as quoted in the press release.
"The goal of all our existing therapies has been to kill as many cells within the tumor as possible," said Wicha. But this study "suggests that the current model may not be getting us anywhere, because we have been targeting the wrong cells with the wrong treatments."
"As few as 100 to 200 of these tumor-inducing cells, isolated from eight of nine tumors in the study, easily induced tumors in mice, while tens of thousands of the other cancer cells from the original tumor failed to do so, Dr. Clarke said. This shows that truly malignant cells are like the proverbial needle in a haystack in the cancer. In the light of these findings, strategies that aim at simply shrinking tumors with radiation or chemotherapy are doomed to failure. They are based on an erroneous understanding of cancer, since size alone is not critical. What is important is killing or restricting these active cancer stem cells.
"[W]e need to develop drugs targeted at the tumor's stem cells," says Dr. Wicha. "If we are to have any real cures in advanced breast cancer, it will be absolutely necessary to eliminate these cells. What this means for women with cancer is that, for the first time, we can define what we believe are the important cells, the cells which determine whether the cancer will come back or be cured," Wicha adds. "Before this, we didn't even know there were such cells."
Cell Surface Markers
Cancer cells have a unique pattern of surface markers on their outer membranes, explained Muhammad Al-Hajj, PhD, a post-doctoral fellow who is first author of the paper. He has compared these surface markers to a person's unique fingerprints. In this experiment, he and his fellow scientists isolated particular sub-populations of cancer cells and then injected these into immune-deficient mice, a standard laboratory technique. These mice were then examined for tumor growth every week for up to six months.
Dr. Al-Hajj found that only a small minority of cells from each tumor were capable of causing new cancers in mice. These really malignant cells had a unique configuration of surface markers: all expressed a protein marker called CD44, in addition to having either very low levels, or no levels, of another marker called CD24.
The fact that tumor-inducing stem cells from eight out of nine women showed a common surface marker pattern is significant, Dr. Wicha explained. "Even though it's only nine patients, it shows that the markers identifying these stem cells were expressed in the majority of breast cancer patients in the study. This may not be the only expression pattern on every patient's stem cells, but it demonstrates the validity of the cancer stem cell model."
The scientists repeated their experiment four times, just to be sure. First, 200 cells with the unique surface pattern were isolated from the original human tumor. After these cells produced a breast tumor in a mouse, Dr. Al-Hajj removed that mouse tumor and used similar techniques to then isolate 200 more stem cells from it. These cells were then injected into another mouse to produce yet another tumor. Once again, that mouse tumor was harvested, malignant stem cells were separated from it, and injected into another mouse. Each such procedure is called a passage. "When we examined the tumors after each passage, we found their cell diversity to be the same as the original tumor," he added.
Drs. Wicha and Clarke believe that it is likely that similar cells drive the development of other types of cancer, as well. "What we are working on now is finding out what makes these tumor stem cells different from the other cells in a tumor," Dr. Wicha said.
Link to Dr. Beard
Last summer, I pointed out in this newsletter that the origin of cancer in the transformation of stem cells was a development anticipated one hundred years ago by John Beard, PhD. Beard, a Professor of Embryology at the University of Edinburgh, Scotland, suggested in a July, 1902 article in The Lancet that cancers arose from 'germ cells' that were left behind in bodily (somatic) tissue during the process of embryo formation. He wasn't just hypothesizing. Using the microscope, he had identified these left-behind embryonic germ cells in the tissues of various experimental animals.
To appreciate the full significance of Beard's theory, it is necessary to understand a little about the early stages of embryonic development. In the very first days of its development, the fertilized egg (called a zygote) cleaves into two cells, which then yield four, then eight. On or about the third day, this pre-embryo becomes a solid little ball of cells called a morula (Latin for mulberry, which it resembles). By the fourth day, this morula becomes a hollow fluid-filled ball called a blastocyst. In the interior of this ball is the inner cell mass, which will eventually become the embryo. But surrounding this mass are specialized cells called trophoblasts, which are ultimately destined to become the placenta. On the sixth day or so, the whole blastocyst burrows its way into the endometrial lining of the mother's uterus by the invasive action of the trophoblasts. In absolute terms, trophoblasts literally make mammalian life possible, since without them the placenta could not form and the blastocyst could never imbed itself into the wall of the uterus.
(It is an extraordinary irony that while trophoblasts enable the fetus to establish itself and to grow to term, these same cells, when they grow at the wrong time and in the wrong place, are responsible for deadly forms of cancer. More about this in next week's newsletter.)
Beard was the first to draw attention to the fact that trophoblasts were virtually identical to cancer cells: invasive, corrosive and metastatic. Other similarities between the trophoblasts and cancer have emerged over the past few decades. For example, trophoblasts produce a hormone known as human chorionic gonadotropin (hCG), which has become the standard biochemical marker of pregnancy. Academic medicine universally acknowledges the origin of a few cancers in germ cells, and recognizes the fact that these and some other cancers produce hCG. However, in the late 1990s Hernan Acevedo, PhD, of Allegheny General Hospital in Pittsburgh, PA, showed that in fact every sample of cancer that he analyzed contained either the beta subunit of hCG or fragments thereof. His discovery was published in the prestigious journal Cancer, and was hailed (by the late Prof. William Regelson) as the discovery of a "definitive cancer marker." But it did not trigger a long-overdue examination of the relationship between trophoblast and cancer.
To view a picture of Dr. John Beard go to:
(NEXT WEEK: I shall continue my discussion of this important finding with an explanation of its implications for cancer treatment. References will be given at that time.)
--Ralph W. Moss, PhD
Ralph W. Moss, Ph.D. Weekly CancerDecisions.com
Newsletter #82 05/04/03
Scientists Identify Stem Cells
As Hidden Cause of Cancer, Part 2
As I discussed last week, Michigan scientists recently announced that a malignant form of stem cells may be responsible for the development of breast cancer. According to a University of Michigan press release, their new understanding is "a paradigm shift in cancer research," and the University has promised to raise $12 million to investigate this concept.
But actually this research has very old antecedents. In 1902, Prof. John Beard of Edinburgh first proposed "germ cells" as the ultimate cause of cancer. These germ cells, he said, were in a sense capable of giving rise to other types of differentiated cells found in an organism. In 1998, mainstream scientists made a huge leap in understanding cancer when they discovered (and patented) embryonic stem cells (ESC). They did not reference Beard in their paper, but they used the term "totipotent" that had often been applied to describe germ cells, meaning that they were capable of developing into any other tissue.
As in the recent Michigan finding, Beard described these aberrant germ cells as a tiny minority of cells with enormous power that are present in a larger mass of reactive tissue. He actually saw these cells in fishes and reptiles and then speculated on their presence in human tissue as well. From their presumed presence in malignant tissue, Beard came to the conclusion that cancer was in essence a single disease which had many manifestations. (A comparable phenomenon would be syphilis, which can manifest itself so differently in so many different organs that it has been called the "great impostor.") From this point of view, the many and varied characteristics of each kind of cancer are due to the interaction of truly malignant cells with neighboring, normal cells and the reaction of surrounding tissues. This takes place under the influence of hormones and cytokines within the microenvironment of each particular organ or tissue. But, according to Beard's theory, the fundamental origin is almost always the same, i.e., it is trophoblastic in nature.
To view a diagram of the development of stem cells click or go to:
Beard said that the first step on the road to cancer occurred when germ cells differentiated into trophoblasts and somatic cells. When that happens in the course of embryo formation, it is necessary and normal. However, when such a process occurs outside the course of pregnancy, the result is what we call cancer.
There are many points of similarity or identity between trophoblasts and cancer cells. As I discussed in last week's newsletter, it has been found that the truly dangerous and malignant portions of breast tumors have a unique configuration of surface markers: all express a protein marker called CD44, in addition to having either very low levels, or no levels, of another marker called CD24. But in a 1996 article, Israeli scientists demonstrated that CD44 surface markers are also found on trophoblasts. "In this study we found human trophoblasts, for the first time, to express CD44," Dr. Ran Goshen and his colleagues at the Hebrew University in Jerusalem wrote. "Intermediate trophoblasts of the first and second trimester exhibited the standard form of CD44...." So here is another important confirmation of the trophoblast-cancer link.
Looked at from a Beardian perspective this uniformity is not surprising. Nor is the fact that the same markers are found in cancers as disparate as leukemia and breast cancer. One can predict that they will now be found in many other cancer types as well. It also helped confirm Beard's theory when modern scientists announced that human embryonic stem cells (ESCs) produce and release the hCG hormone.
As I wrote last year on the 100th anniversary of Beard's discovery, the relationship between Beard's germ cells and contemporary totipotent stem cells deserves further study. More and more, trophoblast and cancer look like two names for the same general phenomenon. Further research will hopefully lead to a revived interest in Beard's contribution, and an incorporation of his powerful ideas into contemporary stem cell research.
Implications for Treatment
It is understandable that U-M scientists, excited by their important findings, would think that an answer to cancer lies in their newly isolated cancer stem cells. The University of Michigan has in fact filed a patent on Dr. Clarke's discovery of stem cells in cancer and Dr. Clarke and his colleagues have also formed a new company called Cancer Stem Cell Genomics (CSCG) to develop and test new therapies to destroy or disable these cells. Dr. Wicha has said that "now that we can actually identify [the cancerous stem cells], we can start developing treatments to specifically target and hopefully eliminate them."
Naturally, I wish them good luck. However, judging from Beard's pioneering work, they may find that there is a missing link in this process. In Beardian terms, the stem cell is like a loaded gun. In and of itself it is not the cause of cancer. What 'pulls the trigger' is the differentiation of the tumor's stem cell into a malignant component of cells that are trophoblast-like in their nature.
In February 1905, Beard theorized that "the secretion of that important digestive gland, the pancreas," could be employed as a natural form of cancer treatment. The first evidence that injections of the pancreatic proteolytic enzyme trypsin did indeed kill cancer cells was published within the following year. In later years, Beard also turned his attention to the carbohydrate digesting enzyme, amylase (which is sometimes overlooked in contemporary enzyme preparations).
In fact, the therapeutic use of pancreatic enzymes flows effortlessly from recognition of cancer as a trophoblast. Beard's reasoning on the subject was as follows. The trophoblast itself is extremely dangerous when it occurs outside the normal placenta. If it overgrows, it forms a kind of cancer called 'choriocarcinoma.' This is a dreaded malignant pregnancy, which (before the introduction of chemotherapy) resulted in the rapid death of both the mother and her fetus. However, Beard said, on the 56th day of gestation the human trophoblast normally stops its progression. What happens on that fateful day? The fetal pancreas starts producing juices containing pancreatic enzymes. Since the fetus doesn't have, or need, a functioning digestive system that early in its development (since all nutrients come to it from the mother, through the umbilical cord) these enzymes have to have another function. Beard's conclusion was that pancreatic enzymes, in addition to their obvious digestive role, also play a role in "digesting" trophoblasts or (later in life) trophoblast-like cancer cells.
In 1911, Beard published his only book, The Enzyme Treatment of Cancer and Its Scientific Basis. His ideas generated considerable attention at the time. The Encyclopedia Britannica (1911) noted:
"Then we have Beard's 'germ-cell' hypothesis, in which he holds that many of the germ-cells in the growing embryo fail to reach their proper position--the generative areas--and settle down and become quiescent in some somatic tissue of the embryo. They may at some later date become active in some way, and so give rise to a cellular proliferation that may imitate the structure in which they grow, so giving rise to new growths."
Beard based his claims not just on laboratory work but on several cases of apparent remission that followed treatment with enzymes. In March 1909, his friend, Captain F. W. Lambelle, MD, then at the Military Hospital in York, treated an ex-drummer of the West Yorkshire Regiment who had a metastatic sarcoma of the left upper jaw. Lambelle gave the man 120 injections of pancreatic enzymes. By the following year, the ex-drummer had completely sloughed off the cancer and remained cancer-free for at least two years. Another cancer - this time a case of breast cancer - was also successfully treated.
However, other physicians were unable to consistently reproduce this work. There were "countless failures," as Beard himself admitted. He believed, with some justification, that commercially available enzymes were of variable quality, and that inadequate doses had often been administered to patients. Due to the lack of reproducible results, interest in his ideas fell away. He died in 1924, a disappointed man. A lifelong bachelor, he left no progeny nor any personal information beyond what can be gleaned from his scientific writings.
Beard's ideas fell out of fashion for many years. But they are no longer entirely strange to the medical establishment. Because of the pioneering work of Nicholas J. Gonzalez, MD, of New York City, the National Institutes of Health (NIH) has invested $1.4 million in an ongoing clinical trial at Columbia University of an enzyme-based regimen as a treatment for advanced pancreatic cancer. One senses that some of the brightest minds in both academic and integrative medicine are converging on a point that will offer tremendous insight and hope in the struggle against cancer.
--Ralph W. Moss, PhD
Acknowledgement: My thanks to Dr. Nicholas Gonzalez, Dr. Michael Clarke and Robert Scott Cathey for helpful comments. Needless to say, any remaining errors are entirely my own.
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Al-Hajj M, et al. From the cover: prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8.
Steinberg D. Stem cell discoveries stir debate. The Scientist 2000;14:1. Accessed at
Thomson JL, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145-7.
Goshen R, et al. Hyaluronan, CD44 and its variant exons in human trophoblast invasion and placental angiogenesis. Mol Hum Reprod. 1996;2:685-91.
U.S. Patent No. 5,843,780, "Primate embryonic stem cells"; accessible at www.uspto.gov.
Beard J. Embryological aspects and etiology of carcinoma. Lancet 1902;1:1758.
Beard J. The Enzyme Treatment of Cancer. London: Chatto & Windus, 1911.
Acevedo HF, et al. Detection of membrane-associated human chorionic gonadotropin and its subunits on human cultured cancer cells of the nervous system. Cancer Detect Prev. 1997;21(4):295-303.
Acevedo HF and Hartsock RJ. Metastatic phenotype correlates with high expression of membrane-associated complete beta-human chorionic gonadotropin in vivo. Cancer. 1996 Dec 1;78(11):2388-99.
Acevedo HF, et al. Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins. Cancer. 1995 Oct 15;76(8):1467-75.
Regelson W. Have we found the "definitive cancer biomarker"? The diagnostic and therapeutic implications of human chorionic gonadotropin-beta expression as a key to malignancy. Cancer. 1995;76:1299-301.
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