Biomedical Engineering Reference
In-Depth Information
original pCSC ''germline'' will be invaluable in understanding pCSCs and
utilizing them to improve diagnostics and prediction of metastasis. If, for
instance, one could isolate the pCSC population or precursors to them, a
more focused gene profile could be used to better determine malignancy and
metastatic potential. This profile could then be used to characterize the cellular
mechanistic origins of increased metastatic capability.
The need to isolate pCSCs for meaningful analysis of prognosis is evident in
breast cancer studies. Markers of pCSCs in solid tumors are still being discovered
and debated, but currently the accepted pCSC markers for breast cancer consist
of overexpression of the cell surface receptor CD44 and low or absent expression
of the anchored membrane protein CD24 (Al-Hajj et al. 2003). It has been shown
that characterization of these markers in whole tumors does not correlate with
metastatic potential or patient survival (Abraham et al. 2005) highlighting the
notion that pCSC may not be equivalent to mCSC. Additionally, some CD44
+
/
CD24
+
cells (in one out of nine breast tumors assayed) have been shown to
induce tumor formation when injected intomouse recipients (Al-Hajj et al. 2003),
implying that these two markers alone may not delineate the pCSC population in
all types of breast cancer. Breast cancer being a widely heterogenous cancer type,
it will be interesting to see if any markers can accurately identify pCSCs across
tumor classes and be used to predict metastatic tendency.
4 Cancer Stem Cells and the Metastatic Cascade
Given that a single cancer cell can drive the formation of a metastatic tumor
(Fidler and Talmadge 1986), CSCs are likely responsible for distant tumorigen-
esis as they are in primary tumor formation. The incongruity between the large
number of malignant cells found in the vascular systems of cancer patients and
the comparatively small number of macrometastases can be reconciled by the
existence of mCSCs. Though other cell subpopulations may break free of the
primary tumor and invade the blood stream, mCSCs, like their pCSC counter-
parts, are those solely responsible for initiation of tumors. mCSCs are related to
pCSCs in essential properties of self-renewal and differentiation needed for the
propagation of the bulk of the tumor, but differ in key ways. Unlike pCSCs,
mCSCs disseminate from the tumor, colonize foreign tissue, and likely have
additional alterations (whether mutational, epigenetic, or adaptive) which
allow survival and propagation in secondary sites. This has been shown in
pancreatic cancer where mCSCs express the same stem cell marker CD133
+
as pCSCs, but additionally express a novel CXCR4 marker known to specifi-
cally effect migration and homing of metastatic cells (Hermann et al. 2007).
The fact that CSCs can be isolated, not only from the primary tumor, but
also from pleural effusions and metastases (Al-Hajj et al. 2003) indicates that
these cells have the capacity to migrate and invade other tissue. A common early
indicator of metastatic breast cancer is the presence of breast cancer cells in the
bones, which in more than 50% of cancers display the CD44
+
/CD24
