Biomedical Engineering Reference
In-Depth Information
binds to DNA in the skin cells, causing a permanent genetic alteration (initia-
tion). However, cancers will not arise unless a proliferative stimulus is subse-
quently given (promotion). This stimulus is provided by treatment of the
initiated skin site with phorbol ester. Thus, the initiation event induces genetic
damage, and the promoter then stimulates the damaged cells to proliferate,
leading to cancer. Initiation must occur before promotion. If promotion is
performed prior to initiation, cancers will not develop. In the original experi-
ments of Peyton Rous (Rous and Kidd, 1942; Friedwald and Rous, 1944),
initiation was accomplished by painting the ear of a rabbit with coal tar. This
produces genetic lesions in the epidermal cells through induction of DNA/
carcinogen adducts that cannot be repaired. If no further insult occurs, tumors
do not develop. However, if the site is wounded by scraping with a cork borer,
epithelial cancer appears at the edge of the wound.
The time between initiation and promotion is the critical element that impli-
cates the stem cell in the skin as the initiated cell. This interval can be days, or even
months or years, in length (Berenblum and Shubik, 1947; Berenblum, 1941, 1954;
Boutwell, 1964; Van Duuren et al., 1975). In order for tumors to grow in this
model, the initiated cells must survive from the time of initiation to the time of
promotion. Given the well-established fact that all cells in the skin, except for the
self-renewing progenitor cells, turn over completely every 2-3 weeks in mice and
about 1 month in humans (Potten andMorris, 1988; Watt, 1989), the only way in
which the initiated cells could still be present, if months or years have passed since
initiation, would be if initiation had occurred in the self-renewing progenitor cell
population. In the course of the year or more between initiation and promotion,
all of the transit-amplifying cells would have been replaced by newly generated
cells from the basal stem cells. Thus, in the initiation-promotion model for skin
carcinogenesis, the initiated cell must be a self-renewing progenitor cell.
2 Cancer Stem Cells
The premise in the preceding section of this chapter was that cancers arise from
stem cells. Now we will discuss in more depth the evidence that cancers also
contain stem cells. Within the last 10 years, there has been an extraordinary revival
of the concept of cancer stem cells (Sell, 2004b, 2006a; Sell and Pierce, 1994; Reya
et al., 2001; Sutherland et al., 1996; Bonnet and Dick, 1997). However, the
biological properties of cancer stem cells have been studied for half a century.
2.1 Properties of Cancer Stem Cells
The critical properties of cancer stem cells are transplantability, the ability to
grow in vitro, and the capacity to survive therapy directed against the cancer
amplifying cells (Buick, 1980).
