Biomedical Engineering Reference
In-Depth Information
model. Overall tumor regression based on size offers no indication that the rare
pCSCs responsible for primary lesion growth or mCSCs responsible for metas-
tasis have been depleted. A better therapeutic endpoint would involve direct
sampling of CSC populations (which would require better markers for fraction-
ing cancer cell populations).
Unfortunately standard treatments have been shown to have little or no
positive effect on CSCs (Hermann et al. 2007; Ho et al. 2007; Hermann et al.
2008; Ma et al. 2008). In pancreatic tumor cells, treatment with the first line
chemotherapeutic agent Gemcitabine has no effect on the CD133
+
population
thought to encompass pCSCs and in mouse models actually leads to enrichment
for this population (Hermann et al. 2008) . CSCs are also resistant to therapeu-
tic levels of radiation in human glioma tumors and treatment causes increased
tumor aggressiveness in some cases (Bao et al. 2006a). The CD44
+
population
in breast cancer also appears to be radio-resistant (Phillips et al. 2006). The
rebound effect seen in all of these models where treated tumors relapse with
greater malignancy could be explained by the fact that chemotherapy and
radiation decrease tumor bulk without affecting CSCs (as shown in Fig. 3),
thereby enriching for the tumor-initiating cells. This response could be attrib-
uted to enhanced DNA repair, anti-apoptotic protein expression, or the pre-
sence of drug-efflux pumps on CSC membranes, all of which have been sug-
gested in various tumor types (Sleeman and Cremers 2007). Furthermore, a new
class of dual-functional genes that contribute to both chemoresistance and
metastasis (Hu et al. 2007) can be enriched in mCSC after therapeutic exposure.
Understanding the metastatic process
reveals
several points at which
