A New View of Cancer's Origins
By Dr. Ralph Moss
from CancerDecisions.com NewsletterGastric cancer originates from bone marrow-derived cells. So states a paper published in late 2004 by scientists at the University of Massachusetts Medical School (UMMS), Worcester, MA. This paper provides a radically different view of how stomach cancer comes into existence and may change the way we view the origin of many other kinds of cancer as well.
The scientists, headed by Prof. JeanMarie Houghton, MD, PhD of UMMS's Gastroenterology Department, discovered an unexpected link between stomach cancer and a type of undifferentiated stem cell that originates in the bone marrow.
They found that an infection with Helicobacter felis (a bacterium related to infectious Helicobacter pylori in humans) leads to an influx of bone marrow-derived stem cells (BMDCs), as the body tries to repair the injury caused by the infection. Prof. Houghton and her colleagues showed that this transformation of BMDCs is the event that actually sparks malignant tumors of the stomach.
In the past, when trying to isolate the source of stomach cancer, scientists focused on damaged cells in the stomach lining. They naturally assumed that stomach cancer was caused by the transformation of normal gastric lining cells into malignant cells. And, indeed, when pathologists look at stomach cancer cells under the microscope, they see something that resembles a misshapen version of normal stomach cells.
However, Prof. Houghton and her colleagues showed that it was these BMDCs, not the stomach cells themselves, that gave rise to cancer. This was an unexpected finding, and might cause a shift in thinking about the formation and progression not only of stomach cancer, but of several other kinds of cancer as well.
"We have known for years that chronic inflammation causes cancer, yet we did not know precisely how," said Prof. Houghton. "Tissue stem cells, which are long-lived cells within organs that act to repair and replenish cells, have long been thought of as targets for carcinogens and the source of cancer. We show that bone marrow-derived stem cells attempt to participate in repair but, under conditions of inflammation, are unable to behave normally and instead progress towards cancer. This dramatically changes the way we think about cancer. If this model applies to human cancer, we will need to revise our approaches to prevention and treatment."
Like other stem cells, BMDCs are pleuripotent – that is, they have the ability to develop into many tissue types. To do so in a normal manner, they require the right environment and the right signals. In an infected stomach, however, the environment itself is diseased; therefore, BMDCs mutate and begin to progress towards cancer.
BMDCs have other cancer-like properties, including:
These properties give them a significant growth advantage, says Prof. Houghton, making them difficult to control once they have mutated.
- the capacity for unlimited growth
- the ability to avoid apoptosis (programmed cell death) signals
- an altered requirement for growth factors
Daring New Model
The authors propose what is a daring new model for the development of at least one major form of cancer.
First, the Helicobacter organism infects the stomach lining and establishes a chronic infection, attended by inflammation. The local immune system is unable to cope successfully. This leads to repeated cycles of injury and repair. The body finally uses up the local supply of stem cells, which normally reside in tissues to cope with just such emergencies. These are in time overwhelmed and compromised by the infection (Anderson 2001)
This exhaustion of the local "police force" calls forth a reserve of special "national guard" cells that have their base camp in the bone marrow. They are specially designed to deal with such persistent threats to health. These are the cells that Dr. Houghton has identified as the BMDC stem cells. They are drawn to, and then engraft themselves into, the beleaguered tissue. But the BMDCs, depending on environmental cues for development and differentiation, encounter an abnormal environment of conflicting growth signals. There follows a downward spiral of metaplasia (the conversion of normal to abnormal tissue); dysplasia (emergence of a precancerous growth); and finally carcinoma (frankly malignant cancer, capable of metastasizing).
Elegant Experiment
In these elegant experiments, scientists used the well established C57BL/6 mouse model of gastric cancer to test their hypothesis. In this experiment, C57BL/6 mice, which are susceptible to Helicobacter induced gastric cancer, had their native bone marrow destroyed by a lethal dose of irradiation. They were then rescued through transplantation of bone marrow from other mice.
This new bone marrow had been genetically engineered to display one of two markers: a protein which fluoresces green, or a distinctive bacterial enzyme called beta-galactosidase which appears blue when stained. No other cells in the mouse's body would pick up this distinctive stain. Additionally, male bone marrow was transplanted into female mice allowing cells to be tracked using detection of the male specific Y- chromosome.
The stomachs of these mice were then infected with a strain of Helicobacter. After six to eight weeks, there was intense die off (apoptosis) of many of the mice's stomach cells, and after about 20 weeks the glands lining the stomach started to stain blue. The number of such blue-staining cells increased dramatically and at one year, 90 percent of the cells within the area of the stomach where cancer forms had been replaced by blue-staining cells. These cells were abnormal, showing signs of metaplasia, dysplasia or outright cancer.
This paper, published in the influential journal Science, thus offers a new model for the origin (pathogenesis) of epithelial cancer. This is not inconsequential, for epithelial cancer is another name for carcinoma, the kind of cancer that affects any tissue covering bodily surfaces and cavities. This category includes not just stomach cancer, but breast, pancreas, colon, etc. – in other words, about 90 percent of all cancers.
Many features of cancer cells become much clearer when viewed within the context of this new model, including their undifferentiated nature; their ability for self-renewal; their resistance to programmed cell death; and their tendency to metastasize and spread quickly. These are some of the key characteristics shared by stem cells and cancer cells.
CAM Perspective
From the perspective of complementary and alternative medicine (CAM), this paper is extremely provocative. Let me offer a few observations:
In their first sentence, the authors state that "the link between infection, chronic inflammation, and cancer has long been recognized." But the theory that cancer can be caused by bacterial infection has not always been accepted so readily by medical authorities.
In fact, many of the researchers in this field suffered instances of "intellectual suppression, particularly when they developed clinical applications," according to Prof. David Hess of Rensselaer Polytechnic Institute, Troy, NY, in his excellent book, Can Bacteria Cause Cancer?
(1997).According to Prof. Hess, "This theory was supported by a rich alternative research tradition that involved at least fifty scientists and clinicians in a number of countries. Popular during the nineteenth century, the theory received continued support during the twentieth century as a minority tradition. Although the quality of the research is very uneven, some of the best of the research has been published in recognized, peer-reviewed scientific journals." (ibid.) There were some fine scientists in this group - such as William B. Coley, MD, Virginia Livingston, MD, and Eleanor Alexander-Jackson, PhD - who provided rigorous demonstrations of the links between various bacteria and cancer.
But the medical establishment essentially banished this theory from the conventional universe of shared ideas. For instance, the concept was severely criticized by Memorial Hospital pathologist James Ewing, MD, the most influential American pathologist of his day. In the first edition of his seminal work, Neoplastic Diseases (1919), Ewing wrote:
"The parasitic [i.e., microbial] theory...appealed to the ancients, was tacitly accepted throughout the Middle Ages, was definitely argued by modern observers, and reached the height of its popularity as a scientific theory about 1895, but during the last fifteen years it has rapidly lost ground, and today few competent observers consider it a possible explanation" of cancer's origins.
Dr. Ewing rejected outright the work of Dr. Peyton Rous of the Rockefeller Institute, who showed, as early as 1911, that sarcoma in chickens could be transmitted by a virus. It took another 55 years for Peyton Rous to finally receive his well deserved Nobel Prize in Medicine precisely for this work.
Similar skepticism greeted Dr. Barry J. Marshall of Perth, Australia, when he argued in the 1980s that Helicobacter could cause gastroesophageal reflux disease (GERD), dyspepsia and stomach ulcers. (It is now understood to also contribute to some forms of stomach cancers.) Marshall's argument was repeatedly rejected out of hand. According to his wife, "The vast majority of the medical profession, not only in Australia but worldwide, considered Barry to be a quack and really were extremely dismissive for a number of years."
It is encouraging that a younger generation of scientists now regards the causative connection between microbes and cancer as non-controversial. But it also needs stating that for many decades, all theories of bacterial involvement in cancer were suppressed and only found refuge within the precincts of the CAM movement. This resulted in damage to the reputations of many fine researchers, a wrong that still needs to be corrected in the historical record.
Unitarian Theory?
Conventional thinking states that cancer is a group of 200 or so different diseases, each of which has its own distinctive features and causes. In this widely accepted model, lung cancer arises from normal bodily (or somatic) cells of the lung, those of the liver from normal liver, and so forth.
In this UMMS experiment, however, Dr. Houghton and her colleagues clearly demonstrated that the cancer developing in the stomachs of the experimental animals - despite every appearance to the contrary - is not really stomach cancer at all. It is caused by the transformation of bone marrow-derived stem cells, which come rushing to the scene in order to help, but are then themselves overwhelmed.
Why then do they look so much like malignant stomach cancer cells that they could fool almost any pathologist who looked at them under the microscope? Probably because these cells develop within the distinctive hormonal "microenvironment" of the organ.
To repeat, these "stomach cancer" cells are masquerading, making themselves appear to be gastric in origin. But their true nature has now been unmasked: they are in reality stem cells that have been transformed under the influence of local infection and inflammation.
It may also turn out that other kinds of carcinoma come about in the same way. In fact, it is possible that this will develop into a model for cancer in general, and that in the future we will no longer be able to talk meaningfully about "stomach," "liver," "breast," or other kinds of carcinoma, but all cancers will be found to have a common origin.
Is cancer then many diseases or one disease with many manifestations? This is one of the oldest debates in oncology. There have been advocates of the single origin (or 'unitarian') theory of cancer, even in conventional medicine. My old boss at Memorial Sloan-Kettering, Lewis Thomas, MD, believed that cancer would eventually be proven to be a single disease. But for a long time, it has been the CAM movement that has provided a refuge for such single-etiology theories.
The classic example of a single, or unitarian, worldview is the trophoblastic theory of cancer. This was essentially propounded in 1902 by the Scottish embryologist John Beard, DSc, and then revived more than half a century ago by Ernst T. Krebs, Jr., and two colleagues. They proposed that all cancer was identical in nature, and that its origin was in generally distributed primordial 'diploid totipotent cells,' which are similar to what are now called stem cells.
Here is what Krebs wrote at mid-century:
"It is veritably impossible to find, among the hundreds of valid experimental contributions to our knowledge of cancer made during the past half century, an experimentally established datum that would controvert the thesis of the basic biological uniformity characterizing all exhibitions of cancer." (Krebs 1950)
This seemed overblown at the time, but more recent work on stem cells at the University of Michigan has shown that it is indeed stem cells, not ordinary somatic cells, that cause breast cancer in another experimental system. Only a tiny minority of cells in these human tumors (growing in immune-deficient mice) are 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, the Michigan professor of internal medicine who directed a 2003 study. "They make copies of themselves - a process called self-renewal – and produce all the other kinds of cells in the original tumor." These really malignant cells 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.
It will certainly be interesting to see if there is a relationship between Dr. Houghton's BMDCs and Dr. Clarke's malignant stem cells. One tell-tale sign would be the presence of these CD44+/CD24- cells. Another would be the expression of chorionic gonadotropin, the characteristic hormone of pregnancy.
These are truly exciting times for cancer research. Investigations of stem cells in many laboratories is homing in on their connection to the origin of cancer. If such modern discoveries could be combined with the rich history and practical experience of the CAM movement, this could lead to a scientifically valid theory of cancer.
Could a cure for cancer be far behind?
Note from Chet: Be sure to sign up for Dr. Moss's excellent newsletter at his website.
References:
Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nat Med. 2001;7:393-5.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet.
2001;357:539-45.Couzin J. Medicine. Tracing the steps of metastasis, cancer's menacing ballet. Science. 2003;299:1002-6.
Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568-71.
Krebs, ET, Jr., Krebs ET, Beard HH. The unitarian or trophoblastic thesis of cancer. Medical Record 1950;163:149-174.
Normile D. Cell proliferation. Common control for cancer, stem cells. Science. 2002;298:1869.
UMMS Public Affairs. Bone marrow-derived stem cells linked to gastric cancers. New thinking on the source of gastric cancer. Nov, 25, 2004. Accessed Feb. 16, 2005. Available here.
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