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Page 2 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

has become generally accepted. Analysis of PubMED reveals the increasing importance of CSCs with over
two thousand publications in 2008 increasing to nearly 7000 annually at the present time and 70,831 in
total. The involvement of the CSC population and their contribution to the circulating tumor cells (CTCs)
and metastatic cancers is also becoming established. After therapy, drug resistant and dormant CSCs
reactivate as major contributors towards tumor recurrence, generating further tumor masses. From this
latter perspective we propose that it will be essential to not only identify the CSCs, but also the means for
selectively targeting these cells to eliminate them if we are to improve upon current cancer therapy. In recent
[1]
years, several reviews have covered the identification of markers for colorectal CSC (CR-CSC) , including
[2-4]
that of the definitive colorectal cancer (CRC) stem cell marker, LGR5 .

In 2010, the question was posed: “How can we identify and analyze colon CSCs and what agents are being
[5]
designed to kill this chemotherapy-refractory population?” . The CSC model accounts for tumor initiation,
metastasis, drug resistance, and relapse and CSCs within the tumor bulk have the capacity to self-renew,
[6-8]
differentiate, and give rise to new tumors (reviewed in ). In the present systematic overview, the focus is
the identification and drug targeting of CSC populations and developing strategies for improving the therapy
of advanced stage colorectal cancer by eliminating CSCs. Controversy has grown around the proposal of
[6]
targeting the CSC population and whether it would be beneficial to patient outcomes . In their treatise on
the problems with the CSC model, these authors pointed out tumor heterogeneity and growth dynamics,
which can be interpreted as cell plasticity in that cancer cells in a more differentiated state can re-enter
the CSC pool. In addition, they argue that targeting a rare population of tumorigenic cells (such as CSCs)
[6]
without consideration of the bulk of proliferating cells may not change patient outcomes . By necessity, the
principle of clonal extinction applies in terms of the need to eliminate all of the cancer cells, including the
[7]
CSCs and their differentiated progenitors if we are to overcome cancer . Simply put, one must kill the roots
of the tree, or it will grow back [Figure 1] and was originally proposed as the “Dandelion hypothesis” for
[8]
CSCs . This will require not only killing the rapidly dividing, more differentiated cancer cell population as
is currently targeted by commonly used chemotherapies, but also the more dormant and drug resistant CSCs
existing within the tumor population.

One of the key aspects of CSCs that should be borne in mind is their property of “stemness” and by this
is meant not only their capability of self-renewal and differentiation, but also that despite being sourced
from different tissue origins, the various types of CSCs with their less differentiated phenotypes, will share
properties and markers in common with embryonic stem cells (ESCs), reflecting their similarity in terms
of earlier stages of development [9,10] . It is only when the CSCs differentiate that they will express greater sets
[11]
of uniquely characteristic markers for the particular cell lineages that they encompass . It is in this light
that the markers for the CR-CSCs are discussed below, and are discussed in reference to related findings of
similar markers found expressed on the ESCs and CSCs alike across a range of different cancer types [9,10,12] .

CSC IDENTIFICATION AND GENERAL DEFINITION
The definition of CSCs is similar to that applied to the normal tissue stem cells: the ability of a small sub-
population of cells existing within a tissue which when isolated and reintroduced into the host have the
capacity to reform complete tissues containing the range of cellular phenotypes similar to the original tissue
from whence the stem cells were derived [12,13] . Thus, CSCs possess characteristics associated with normal
stem cells, specifically mulitpotency in the ability to give rise to all cell types found upon pathological
[11]
examination of an excised tumor . The most commonly used method for identifying and isolating CSCs
is via their characteristic cell surface markers, many of which were originally discovered from studies of
normal tissue development, including from hematopoiesis and embryonic stem cells and which are also
[9]
found co-expressed on CSCs .

The major surface markers that have been used to identify colorectal CSCs to enable their definitive isolation
are the focus of this review, as well as improved means for testing anticancer cytotoxic drugs targeting