Cancer Decisions - Free Newsletter

Scientists Identify Stem Cells As Hidden Cause of Cancer

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

Dr. John 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 (pictured right), 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.

(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, Ph.D.

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The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.