Biomedical Engineering Reference
In-Depth Information
13.1 Cancer Therapy ''Causes'' Cancers
If most solid tumors are composed of a minor population of self-renewing
(stem) cells and a large fraction of non-renewing cells, cancer therapy failure
following radiation and chemotherapy treatments is not the result of a rare cell
evolving from within the tumor, but the regrowth of the cancer stem cells. Of
course, tumor stem cells could accumulate genetic changes rendering them even
more drug resistant, radiation resistant, or aneuploid. Because cures are
achieved for many types of cancer, the cancer stem cells must be eliminated
by a given therapeutic strategy. Mature, committed stroma in the tumor micro-
environment are likely to play a role in supporting or stimulating the stem cells,
forming a ''tumor niche''. The rapid regression of the tumor could lead to
disruption of the tumor niche and the elimination of the cancer stem cells.
Immune surveillance is clearly important in many cancers (Nakachi et al.,
2004), and reducing the mass of the tumor may allow the immune system to
efficiently recognize the remaining cells.
Targeted therapies directly suppressing or killing tumor stem cells may
synergize with established therapies to provide increased efficacy. Angiogenesis
is likely to be critical to provide blood supply to the tumor stem cells, and
strategies to inhibit the development of blood vessels are likely to be effective
(Folkman, 2002).
One of the protective mechanisms of stem cells against toxins is the expres-
sion of one or more ATP-binding cassette (ABC) efflux transporters. These
pumps protect stem cells from xenobiotic toxins (Gottesman et al., 2002). The
ABCG2 and ABCB1/MDR1 genes are expressed in the majority of stem cells
and in most tumor stem cells (Kim et al., 2002; Scharenberg et al., 2002; Zhou
et al., 2001). These transporters can efflux fluorescent dyes such as rhodamine
andHoecht 33342, and this property allows stem cells to be separated from non-
stem cells on a cell sorter (Goodell et al., 1996). The combined use of che-
motherapy drugs and ABC transporter inhibitors could be used to specifically
target cancer stem cells (Dean and Annilo, 2005). There are highly specific
inhibitors of ABCB1 in clinical use and ABCG2 inhibitors in development
(Henrich et al., 2006). Transporter inhibition therapies are likely to have toxic
effects on the patient's normal stem cells, and both ABCG2 and ABCB1 play a
role in the blood-brain barrier. Therefore, this approach would have to be
carefully adjusted to avoid excessive toxicity.
14 How the Stem Cell Paradigm Suggests New Approaches
Another approach to inhibiting cancer stem cells is to target the proteins
essential for the growth and maintenance of stem cells. Because of the funda-
mental research in Drosophila, mice, C. elegans, zebrafish, and other develop-
mental systems, a tremendous amount is known about the growth regulatory
