Biomedical Engineering Reference
In-Depth Information
3.1 Clonal Stem or Precursor Cell Expansion Initiates Adenoma Formation . . .
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3.2
Identification of Initiators of Clonal Growth . . . . . . . . . . . . . . . . . . . . . . . . .
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3.3 Adenoma to Carcinoma Transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4
Identification of Colon-Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.1 Colon-Cancer Stem Cells: Definition and Methods . . . . . . . . . . . . . . . . . . . .
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4.2 Colon-Cancer Stem Cell Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.3
In Vivo Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.4 Caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5
In Vitro Expansion of Colon-Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . .
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6 Origin of the Colon-Cancer Stem Cell
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7 Cancer Stem Cells in Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8 Consequences of the Cancer Stem Cell Model for Therapy . . . . . . . . . . . . . . . . . .
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8.1 Minimal Residual Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8.2 Chemoresistance of Colon-Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . . . . .
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8.3 Development of New Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 Introduction
Colorectal cancer (CRC) is the second most common cause of cancer death in the
Western world with an estimated worldwide incidence of almost 1,000,000 per
year (Mathers and Boschi-Pinto, 2006). This high prevalence and the easy acces-
sibility of the colon for tissue sampling have contributed to the fact that CRC
is one of the best studied malignancies. The development of a CRC involves a
histopathological sequence of events caused by the stepwise genetic and epigene-
tic alteration of the expression of oncogenes and tumor suppressor genes. This
succession of events has been dubbed the adenoma-carcinoma sequence (Fearon
and Vogelstein, 1990). How these genetic changes drive the clonal proliferation of
mutant colonic epithelial cells in adenomas and later in carcinomas remains an
area of intense investigation. New insights from the up-and-coming field of cancer
stem cell research may help to clarify how different oncogenes and tumor sup-
pressors regulate clonal growth in the adenoma to carcinoma sequence.
The cancer stem cell model of colon carcinomas views a CRC as a hierarchical
organized entity with a rare population of cancer stem cells driving tumor growth
and progression (Vermeulen et al., 2008). Cancer stem cells can both expand in a
clonal manner to generate more cancer stem cells and generate the more differ-
entiated cells present in a CRC. It is believed that those differentiated cells have
lost the potential to self-renew and subsequently the capacity to promote tumor
growth in the long run. This new concept in colon-cancer biology has widespread
consequences for the way we view this malignancy with respect to tumor initia-
tion and progression of the disease and for the understanding of the mode of
action of currently existing therapies for CRC and the design of future therapeu-
tic modalities. Although useful when considering the biology of a colorectal
cancer, the term colon-cancer stem cell unfortunately cannot be used for the
adenomas that precede the cancer stage. Most colonic clonal growths
