Biomedical Engineering Reference
In-Depth Information
when manipulated in vitro can sometimes take on stem cell qualities of plur-
ipotency and self-renewal (Wernig et al. 2007). Some argue that these are not
physiologically relevant phenomena in that they require much cell manipula-
tion, yet they are interesting findings in light of the search for the origins of
pCSCs. Though terminally differentiated cell types are unlikely candidates for
pCSC formation, studies seeking the sources of pCSCs have found evidence for
both stem cells and progenitors (Cairns 2002; Stingl and Caldas 2007).
Normal adult stem cells are likely candidates for pCSC precursors. The most
obvious line of evidence for this possibility is that qualities which define a stem
cell (self-renewal and differentiation) are also the characteristics that define a
CSC. Cancer formation as a step-wise process also requires time for mutations
to accumulate. Owing to their inherent self-renewal, stem cells undergo many
cell divisions over a long period of time in which multiple DNA-replication
mistakes and sporadic mutations can be compounded. Connections between
normal and cancer stem cells can also be made through common signaling
pathways that have been discovered to mediate function of both cell types. It
has been known for many years that Wnt, Notch, Hedgehog, and Bone Mor-
phogenic Protein (BMP) signaling cascades regulate growth and differentiation
of normal stem cells. All of these signals have a dual role in that they also affect
self-renewal, tumor growth, and malignancy in various cancer models (Piccirillo
et al. 2006). Cell surface markers suggest that normal stem cells may give
rise to their cancerous counterparts. In hematopoietic cancers, the surface
marker signature for normal tissue stem cells CD34
+
CD38
Thy1
Lin
also
identifies CSCs (reviewed in Lin and Sessa 2004). It should be mentioned that
cell surface marker similarity could arise from progenitor cells re-adopting stem
cell markers during tumorigenic growth as has been shown in some normal
epithelial cells of the hair follicle (Ito et al. 2007), although few other precedents
exist for this phenomenon. Expansion of mammary stem cell populations in
mice precede cancer formation, strongly suggesting a role for normal tissue
stem cells in the development of malignancies (Shackelton et al. 2006). While
this finding has been recently expanded to other cancer model systems (Miya-
moto et al. 2000; Kim et al. 2005) there is still no direct connection between
adult stem cells and pCSCs. Conclusive evidence would consist of direct trans-
formation of stem cells into pCSCs capable of propagating tumors which may
have varying degrees of malignancy. Until researchers are able to better identify
and isolate stem cell populations, as has been done in the hematopoietic system,
this goal will remain elusive. The difficulty lies in the relative scarcity of stem
cells and paucity of reliable in vivo models to isolate them as compared to
committed progenitors. Based on their relative abundance, it is possible that
committed progenitors cells are more likely to be the population that gives rise
to pCSCs.
Since progenitor cells occur typically with much more frequency in adult
tissues, statistically they are more likely to sustain the types of oncogenic
mutations characteristic of cancer. Strong evidence, especially in leukemias,
suggests progenitors as pCSC precursors. In patients with human acute
