Biomedical Engineering Reference
In-Depth Information
cancer stem cells are the cells responsible for long-term tumor growth and the
formation of metastasis, then this is the clinically relevant population to target.
At present new drugs are initially evaluated in late-stage patients and the most
important parameter is tumor response. This leads to a selection of drugs that
effectively target the bulk of tumor cells. This is a possible explanation for the
so-called survival paradox, the fact that tumor response does not correlate very
well with survival in cancer patients (Huff et al., 2006). Possibly promising new
drugs that effectively target the cancer stem cell population are missed because
of their limited effect on tumor volume in the short term, while on the contrary
drugs are approved that reduce tumor mass but do not target the clinical-
relevant population of cancer stem cells.
9 Synthesis
Stem cells in the normal colon occupy a niche at the bottom of the crypt. The
expansion of these stem cells is highly regulated; under homeostatic conditions
the stem cells and their transit-amplifying cells are tightly topographically
restricted to their niche. However, stem cells can expand in a clonal manner
under both physiological and pathophysiological conditions. Regulated clonal
expansion of stem cells is observed during postnatal growth and in situations of
damage and repair. Deregulated clonal expansion is the hallmark of the ade-
noma to carcinoma sequence that leads to colorectal cancer development. Both
forms of clonal expansion are characterized by crypt fission. There is a close
resemblance between the mechanism of crypt fission during intestinal repair
and that observed in early-stage adenomas. The clonal expansion that is char-
acteristic for the growth of early adenoma formation is therefore probably best
seen as the unrestrained activation of a physiological repair mechanism.
Research in the past decade has shown that colonic stem cell behavior is strictly
controlled by the same morphogenetic signaling pathways that specify cellular
fate during development. Mutations in these pathways lead to adenoma and
hamartoma formation.
From histological examinations it is clear that an early adenoma is not a
homogeneous mass of proliferating cells but a hierarchically organized lesion
with proliferating cells and more or less differentiated derivatives. As an ade-
noma progresses to cancer and a cancer progressively becomes less differen-
tiated this may become somewhat less straightforward but it is still clear from
the pathology of most colorectal cancers that they do not look like homoge-
neous masses of cells but that clear heterogeneity in morphology and marker
expression can be detected. Exciting new experimental data now show that cells
in a colorectal cancer not only look heterogeneous but are, in fact, also func-
tionally very distinct. Only a small population of immature cancer cells, dubbed
cancer stem cells, can propagate a tumor in immuno-compromised mice
whereas most cells in the tumor cannot. Furthermore, these cancer stem cells