Biomedical Engineering Reference
In-Depth Information
CSCs in breast cancer metastasis. Further exploration of CD44 inhibition may
result in powerful anti-metastatic drugs in multiple cancer types. Another
potential target is CXCR4 which is important in cancer metastasis of breast,
prostate, and other cancers (Muller et al. 2001; Taichman et al. 2002; Kang et al.
2003), in pancreatic mCSCmetastasis (Hermann et al. 2007), and in adhesion of
hematopoietic tumor cells to their putative niche (Tavor et al. 2004). Metastatic
niche signaling pathways that promote proliferation and downregulate differ-
entiation will also be interesting targets for molecular intervention. Further
characterization of these interactions is needed to specifically block metastatic
growth without adversely affecting large numbers of adult stem cells which rely
on the same signaling molecules for normal function.
6.2 Transition of Quiescence (Micrometastasis) to Proliferation
(Macrometastasis)
It is theorized that mCSCs disseminate from the primary tumor, potentially in
the early stages of growth, and lodge in secondary sites where they can remain
dormant. Latency between migration and metastatic growth could be deter-
mined by induction signals in the pre-metastatic niche. While this process has
yet to be confirmed, reactivation signals would be an ideal target for drug
interference. By the time a tumor is detected it is likely that mCSCs have already
invaded and adhered to distant organs, reducing the efficacy of drugs interfer-
ing with mCSC migration or adhesion. Currently reactivation of mCSCs
remains a theory and effective drugs remain far in the future. Nevertheless it
remains an exciting possibility and an area for innovative research.
6.3 Targeting CSC Surface Markers
Cell surface markers (such as CD133 in pancreatic tumors and CD44 in breast
cancer) generally used to identify mCSCs could also be used to target these cells
for clearance from the body. DNA vaccines and oncolytic virus approaches
could be useful in selectively killing these most dangerous cells. Some evidence
for potential in this direction has been shown in breast cancer pleural effusions.
When CD44
+
/CD24
cells are infected with adenoviruses with modified capsid
protein they lose their ability to generate tumors (Eriksson et al. 2007). The
same viruses can deplete the population of CD44
+
/CD24
CSCs in established
tumors. As opposed to non-specific chemotherapy or radiation, this type of
treatment could decrease the risk of recurrence and rebound effects. Caveats to
this approach include incomplete understanding of marker specificity and the
fact that normal stem cell populations often share surface markers with CSCs.
Further research is essential to finding ways to exploit surface markers without
depleting systemic levels of adult stem cells.
