Page 34 - Read Online

Page 4 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

case of leukemias, only a few cancer cells isolated from the blood of leukemic animals were sufficient for
[16]
transferring the leukemia into naïve healthy animals receiving the transfused cells . Thus arose the basis
for disputing the very existence of CSCs and whether all cancer cells are self-endowed with the capability of
giving rise to whole tumors.

Since the discovery of CSCs, we have witnessed further complexities with the emergence of the epithelial to
mesenchymal transition (EMT) hypothesis by which it was proposed that tumor cells transit back and forth
between the two different states during the processes of invasion, migration and metastasis to form tumors
[17]
at distant sites . However, this view has been made less certain given recent evidence showing that multiple
phenotypes are present within both the tumors and CTCs, which exist rather as mixtures of cells including
[18]
both epithelial and mesenchymal types . The emerging evidence from a range of studies would rather
suggest a dynamic tumor heterogeneity with cancer cell plasticity existing as the consequence of genetic and
metabolic changes, environmental differences and reversible adaptation of cellular properties, all proceeding
within the context of a heirarchical system of tumorigenic CSCs differentiating into non-tumorigenic
progeny (for reviews, see [19-21] ).

During the course of progession within the primary tumor microenvironment, with expanding growth
and increasing cellular demands on the limited availability of nutrients and oxygen supply, there follow
frequent rounds of intermittent hypoxia, hypoglycemia and acidosis occurring within the tumor
[22]
microenvironment . Such conditions are the drivers for the production of greater numbers of the CSCs as
[23]
a percentage of the total tumor population (reviewed in ). In addition, such stressors within tumors give
rise to cancer cells showing a higher capacity to invade into nearby tissues, extending beyond the tumor
boundary, migrating from the site of the primary tumors into the circulatory system to produce metastases.
In this manner, the tumor spreads into distant locations, some involving advanced release of exosomes,
interactions with immune cells and extracellular matrix to lay down the framework for future tumor beds at
[24]
these remote sites as premetastatic niches .
Recent evidence has shown that the CTCs have a stem cell phenotype as evidenced by their expression of
[25]
embryonic transcription factors (including OCT4, SOX2 and NANOG ), and contain mixtures of epithelial
and mesenchymal phenotypes (reviewed in [26-28] ). Furthermore, analyses of CTCs derived from the peripheral
[28]
blood of colorectal cancer patients showed that they exhibit a more CSC-like phenotype , including
expression of CSC markers such as LGR5, establishing these as prognostic markers for disease progression
and metastasis in CRC patients. From these observations, it would appear that the CTC population includes
CSCs in their mix and that such cells are highly metastastic [Figure 2]. Despite these complexities, our ability
to identify and target the CSC populations with specific cytotoxic drugs must improve if we are to eliminate
the cause of cancers and their metastasis, given their significantly enhanced tumor-initiating potential.

CR-CSCS, WNT SIGNALLING AND SURFACE MARKERS IN COMMON WITH OTHER CANCER
TYPES
The self-renewal of CSCs is regulated by various modulators, including WNT/b-catenin, Notch and Hedgehog
signalling, and at the transcriptional level by the pluripotency transcription factors such as OCT-3/4, KLF4,
[29]
SOX2, and c-MYC, chromatin remodeling complexes, and non-coding RNAs (reviewed in ). WNT
signalling cascades cross-talk via the fibroblast growth factor (FGF), Notch, Hedgehog and transforming
growth factor beta (TGFb)/bone morphogenetic protein signalling cascades to regulate expression of the
functional CSC surface markers that have been identified, such as CD44, CD133 (PROM1), epithelial cell
[30]
adhesion molecule (EPCAM) and LGR5 (GPR49) (reviewed in ). The CSC regulatory signalling pathways
such as WNT have become a target with implications for therapeutic interventions in cancers, albeit that its
[31]
complexity poses significant challenges . The WNT/b-catenin pathway is involved in the regulation of CSCs
as with normal stem cells and their differentiation during embryogenesis and in the adult [30,31] .