Download Cancer stem cells revisited

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PIPES and ABLIN
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Cancer stem cells
revisited
B.L. Pipes MS* and R.J. Ablin PhD*,†
Stem cell research is currently at the frontier of medical science. Embryonic stem cells, therapeutic cloning, tissue regeneration—research into the vast
therapeutic possibilities inherent in understanding and
manipulating stem cells is exploding. Amid all this
activity, understanding of the role that stem cells play
in carcinogenesis has also been increasing.
Stem cells have an extended replicative lifespan,
which makes them excellent candidates for the cell
of origin of cancer. The standard multi-step somatic
mutation theory of carcinogenesis requires that a cell
acquire several critical mutations in the cell cycle or
proliferation pathways, or both 1. The extended replicative lifespan of stem cells, or of primitive progenitor cells, would provide the opportunity over the
lifespan of an individual for these rare, random mutations to accumulate in a cell.
As reasonable as this argument seems, stem cells
as the cell origin of cancer is not currently a favoured
model. Although a stem-cell origin of cancer was
initially proposed more than thirty years ago 2, research in this area has been overshadowed by massive amounts of work focussed on elucidating the
genetic mechanisms of the underlying somatic mutation theory. The reasons for this focus, as addressed
by Sonnenschein and Soto 3, are complicated and
controversial.
Until very recently, a stem- or progenitor-cell
origin in carcinogenesis found support only in leukemia research. There, it was first accepted that both
hematopoetic stem and progenitor cells could acquire
genetic abnormalities that would lead to the uncontrolled replication and dysregulated differentiation
that are characteristic of the spectrum of leukemic
cancers 4,5. The possibility that a similar stem-cell
origin of carcinogenesis might apply to solid malignant tumours was not vigorously pursued and has
only recently been experimentally addressed.
In 2003, Al-Hajj et al. 6 provided the first evidence for the existence of breast cancer stem cells.
They identified a subpopulation of tumour cells that
was 10 – 50 times more tumorigenic in xenografts
than were cells from the bulk of the tumour. The cells
in this subpopulation were also able to give rise to
further tumorigenic cells—and to partially differentiated, non-tumorigenic cells. Continued experimental investigations of these breast cancer stem cells 7,8
have lent considerable support to the theory of a stemcell origin in carcinogenesis in solid malignant
tumours. Currently, intriguing evidence is also coming from other investigators for the existence of stemcell involvement in several other solid malignancies,
including those of prostate, ovary, lung, and brain 9,10.
An unexpected twist to the model of stem-cell
carcinogenesis was revealed in a study of gastric cancer 11, wherein the cell of origin of the cancer was
found to be not only a stem cell, but a stem cell derived from bone marrow, not from gastric epithelium!
The foregoing findings, together with data from
earlier studies by one of the present authors (RJA),
have been incorporated into a revised theory of the
stem-cell origin of cancer, in which circulating bone
marrow–derived stem cells may become tumorigenic
in a variety of chronically inflamed tissue compartments 12. Future work will reveal if bone marrow–
derived stem cells or local-tissue stem cells are indeed
the origin for many, or perhaps most, human epithelial cancers.
As the current explosion of interest in stem cells
and their therapeutic possibilities continues, the
knowledge gained should stimulate further interest
in developing the stem-cell theory of carcinogenesis.
Whatever the exact involvement of stem cells in the
origin of cancers is ultimately found to be, the great
hope is that new therapeutic approaches targeting the
cancer stem cells within tumours will, in conjunction with current therapies that target the bulk of the
tumour, provide oncologists with improved armaments in the war against cancer.
REFERENCES
1. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Speciesand cell type–specific requirements for cellular transformation. Cancer Cell 2004;6:171–83.
2. Pardal R, Clarke MF, Morrison SJ. Applying the principles of
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EDITORIAL: CANCER STEM CELLS REVISITED
stem-cell biology to cancer. Nat Rev Cancer 2003;3:895–902.
3. Sonnenschein C, Soto AM. Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinogen 2000;29:205–11.
4. Gilliland DG, Jordan CT, Felix CA. The molecular basis of
leukemia. Hematology (Am Soc Hematol Educ Program) 2004;
:80–97.
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Hematology 2005;10:349–59.
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pathways, and carcinogenesis. Breast Cancer Res 2005;7:
86–95.
8. Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro
propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005;65:5506–11.
9. Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis
identifies a death-from-cancer signature predicting therapy
failure in patients with multiple types of cancer. J Clin Invest
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10. Fomchenko EI, Holland EC. Stem cells and brain cancer. Exp
Cell Res 2005;306:323–9.
11. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow–derived cells. Science 2004;306:
1568–71.
12. He X, Tsang TC, Pipes BL, Ablin RJ, Harris DT. A stem cell
fusion model of carcinogenesis. J Exp Ther Oncol 2005;
5:101–9.
Corresponding author: Brian L. Pipes, Department
of Microbiology and Immunology, University of
Arizona College of Medicine, Tucson, Arizona 85724-5049 U.S.A.
E-mail: [email protected]
*
†
Department of Microbiology and Immunology,
University of Arizona College of Medicine, Tucson, Arizona, U.S.A.
Arizona Cancer Center and Center for Injury
Mechanisms and Related Responses, University
of Arizona College of Nursing, Tucson, Arizona,
U.S.A.
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