Deciphering Fate Decision in Normal and Cancer Stem Cells: Mathematical Models and Their Experimental Verification - Mathematical Methods and Models in Biomedicine - page 198

3 Cancer Stem Cell Theory

The CSC theory asserts that some elements of the normal cellular hierarchy exist
also in cancer. The theory states that in cancerous tissue, as in normal tissue, a
small percentage of cells possess the ability of unlimited self-renewal [ 6 , 18 , 75 ].
These cells, called CSCs, drive the growth and spread of the disease, whereas their
more differentiated progeny are destined to die, as they have limited or no ability to
undergo further mitotic divisions [ 57 ]. It was originally postulated that CSCs arose
from normal SCs that escaped the bounds of self-renewal [ 29 , 52 ]. However, it is
also possible that these cells are the result of mutations that caused a progenitor cell
to reacquire the ability of self-renewal [ 18 ].
In the 1990s, studies in patients with chronic myelogenous leukemia (CML)
and acute myelogenous leukemia (AML) provided compelling evidence for the
existence of CSCs [ 11 , 29 , 88 ]. Since then, cells with SC characteristics have been
identified in solid cancer diseases, such as brain cancer and breast cancer. Putative
SC populations have also been observed in cancer types such as colon, pancreas,
prostate, and melanoma (see review by Lobo et al. [ 57 ]). However, there is still
controversy about the generality of the CSC theory [ 1 , 42 ].
CSCs seem to be relatively resistant to conventional therapy. In several in vitro
experiments, putative SCs in different cancer types, for example multiple myeloma
and breast cancer, did not respond to conventional chemotherapeutic agents [ 56 , 62 ].
Radioresistance was also shown for ex vivo Glioma stem cells [ 9 ]. This may
be because CSCs have a slow proliferation rate, in comparison to differentiated
transiently amplifying tumor cells, while chemotherapy and radiotherapy generally
target rapidly proliferating cells [ 92 ]. Moreover, owing to their limitless replication
capacity, CSCs that have survived treatment are capable of replenishing a depleted
tumor. This may explain the high occurrence of cancer relapse after seemingly
successful therapy with strong clinical response [ 66 ]. According to this hypothesis,
effective tumor eradication must include agents that target CSCs [ 23 ]. Recently,
outcomes of clinical trials in both myeloma [ 40 ] and breast cancer [ 21 ] patients have
supported this theory by showing correlation between CSC quantities and patient
survival after treatment.
Agents that efficaciously attack CSCs and cause their death (elimination therapy)
are scarce, owing to these cells' resistance to drugs. Alternative therapy modalities
that target CSCs include inhibiting CSC proliferation (inhibition therapy), or
driving them to differentiate into transiently amplifying tumor cells (differentiation
therapy), which leads to their terminal differentiation and eventual death and
facilitates their elimination through conventional therapy [ 78 ].
CSC theory suggests that cancerous tissues might have some kind of homeostatic
regulation analogous to that in normal tissues. Thus, an understanding of fate
decision mechanisms can shed light on CSC population sizes and dynamics, just as
it can for SCs in normal tissue. Some of the main signaling pathways that participate
in the regulation of SC fate decision in developmental processes have been found