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| SYNOPSIS |
Vancouver
Although the link between Helicobacter pylori infection and gastric cancer is well established, new research suggests that stem cells play an important role in the development of this malignant disease. JeanMarie Houghton and colleagues recently showed that H. pylori-induced inflammation in mice caused the migration of stem cells originating from bone marrow to the stomach, where they subsequently developed into gastric tumours.1Previous evidence suggests that bone-marrow-derived cells have a reparative function on being recruited to areas of injury or inflammation. The idea that these cells might also play a role in the development of cancer revisits a concept that arose partly from the observation in the 1970s that only 1% of leukemia cells grow into colonies in vitro, an ability that later earned these cells the label "cancer stem cells."2 Houghton and colleagues' research suggests that similar stem cells may give rise to gastric cancer, a finding that presents a new way of thinking about the pathogenesis of a disease that is the second leading cause of cancer-related deaths worldwide, killing nearly 600 000 people each year.
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H. pylori and cancer
H. pylori is one of the most common chronic bacterial infections worldwide. The bacterium is the only one known to consistently tolerate the acidic environment of the stomach. Without treatment, H. pylori infection can persist for many years, causing chronic inflammation.
Up to 80% of patients with gastric cancer have a current or past H. pylori infection.3 This has led the World Health Organization to classify H. pylori as a group 1 carcinogen (www.cie.iarc.fr/monoeval/crthgr01.html). How the bacterium contributes to the development of cancer is still not entirely clear, although bacterial proteins, the immune response and hormonal responses have all been implicated. In addition, current research is beginning to link inflammation to the formation of tumours, with the inflammation-induced protein NF-kB emerging as a key factor.4
Are stem cells to blame?
Houghton and colleagues' work suggests an unexpected alternative to the inflammation theory. The research group focused on the idea that bone-marrow-derived cells move into areas of chronic injury or inflammation to effect repairs. What long-term consequence this recruitment has on chronic inflammation is largely unknown. Houghton and colleagues wondered if these stem cells could be involved in the development of gastric cancer.
To study this question, Houghton and colleagues used a strain of mice (C57BL/6) and a relative of H. pylori (H. felis) that together form a well-established model of gastric cancer in humans. They irradiated the mice to destroy their natural bone-marrow-derived cells, replacing them with transgenic cells that would express easily detectable markers. Six to 8 weeks after the infection of these transgenic mice with H. felis, Houghton and colleagues began to detect bone-marrow-derived cells migrating into the stomach lining, presumably to repair the damage caused by the bacteria; by 20 weeks, the labelled cells were differentiating into cells with the characteristics of stomach epithelial cells.
But the authors found that these differentiating cells looked odd and behaved abnormally: they began to elongate, branch, crowd together and become distorted, and their growth rate started to accelerate. After 52 weeks, the mice were in the early stages of developing gastric cancer, and the tumours that subsequently formed stained positively for markers that indicated that the cells indeed came from the bone marrow.
Stem cells are often touted as holding great promise for novel therapies for problems ranging from myocardial infarction to Alzheimer's disease and parkinsonism. However, a recent revival of an old concept that stem cells may be the cellular origin of cancer is bringing a note of caution to the idea of using them to repair organs. (Cohnheim and Durante hypothesized 150 years ago that cancer might arise from embryonic stem cells, since the 2 types of tissue resemble each other.5) This revival got a jumpstart in 1997, when Bonnet and Dick6 from the University of Toronto made dilutions of leukemia cells to reveal that approximately one in a million had the ability to reproduce the disease, suggesting the presence of a "cancer stem cell." Similarly, Houghton and colleagues' work suggests that bone-marrow- derived cells are cancer stem cells for gastric tumours.
However, this one study does not provide definitive proof, and more work is needed to show that the bone-marrow-derived cells in their model did indeed differentiate rather than merely fusing with epithelial cells. Furthermore, there is as yet no way to determine whether bone-marrow-derived cells cause gastric cancer in humans, since no markers are available. Nevertheless, these findings are a warning against the premature development of stem cell therapies and are bound to spark debate on the pathogenesis of gastric cancer.
References
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Copyright 1995-2005, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
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