Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

The gastrointestinal tract (GIT) contains cells that rapidly divide and turn over, which contribute to diverse functions and are supported by intestinal stem cells (ISCs) located at the crypt bottom. It is possible that the presence of a rapidly proliferating epithelium in the gut and frequently dividing ISCs might increase the propensity for malignant transformation in the organ. Globally, colorectal cancer (CRC) is one of the most common forms of cancer and the second leading cause of cancer mortality in Europe and the United States (Siegel et al., 2014). The clonal selection model that was formed in 1975 has been the main paradigm by which to describe the emergence of CRC; further characterization of the genetic mechanism that drives colorectal carcinogenesis and progression was made by Bert Vogelstein during the late 1980s and early 1990s (Fearon and Vogelstein, 1990; Puglisi et al., 2013). CRC develops from epithelial cells covering the GIT, as they undergo sequential mutations of the genes that control proliferation, self-renewal and evasion of cell death and the immune system. This model remains the hallmark for understanding the pathogenesis of the disease today. However, it is clear that CRC is a complex disease with several molecular subtypes, and the mechanisms that underlie its intratumoural and intertumoural cellular heterogeneity and which may cause treatment failure remain to be elucidated. There is increasing evidence to suggest that human cancer can be considered a stem cell disease and that not all cancer cells may be equally malignant. There is also growing support for a cancer cellular hierarchical model that assumes that the cancer cells that form a tumour are hierarchically ordered and that only a rare undifferentiated cell present at the apex of this hierarchy has the unique biological properties necessary for tumour initiation, maintenance and metastasis (Puglisi et al., 2013). Provided the characteristics of such cells exist and can be validated, they are considered to be colorectal cancer stem cells (CRCSCs). CRCSCs are believed to contribute to tumour heterogeneity and repopulate the tumour (with a treatment-refractory population of tumour cells) following perturbed tumour homeostasis as a result of, say, cancer therapy. This type of hierarchical model suggests that there are cells within a tumour that harbour different tumourigenic potentials. Certain cells may lose their tumourigenic potential, while others may retain it; such tumour cell populations have been identified in solid and haematological malignancies (Puglisi et al., 2013). Thus, there appear to be several conceptual similarities between normal nonmalignant ISCs and CRCSCs. The concept is based upon a view of carcinogenesis as an aberrant form of organogenesis. Furthermore, the long life and capacity for self-renewal of CRCSCs may hint towards a commonality with the stem cells of normal tissues. Thus, it becomes tempting to draw a linear connection between ISCs in the normal gut and CRCSCs in the tumour. It would appear to be thermodynamically favourable if genetic and/or epigenetic alterations were to contribute to the transformation of an ISC into a CRCSC, whose progeny would constitute the majority of different tumour cells making up the bulk of the cancer. Thus, an ISC could be the progenitor to the CRCSC population in cancers of the gut. However, such an assumption is fraught with pitfalls and is currently not sufficiently supported by evidence, and it also does not exclude the possibility that

a CRCSC might arise from a reprogrammed differentiated cell. It has been proposed that a high level of plasticity exists between ISCs and early progenitor cells (transit-amplifying cells, TACs) in the normal small intestine of the mouse (Barker et al., 2012). Thus, it appears that progenitors may redifferentiate to ISCs and therefore that no obligate irreversible boundary exists between progenitor cells and stem cells in the gut. It is tempting to speculate that redifferentiation might occur in a similar manner in CRCs or might even be less stringently controlled in such tissues, considering that the dependency on extracellular growth signals is often lost in advanced malignancies. The genetic lesions that allow cancer cells to proliferate autonomously may allow such cells to wean themselves off the stem cell niches that are crucial for the maintenance of a population of ISCs in the normal gut. Thus, the identity of the normal tissue-originating cell of CRCSCs remains unclear in CRC. The stem cell theory may also have important translational implications, since further understanding of the behaviour of ISCs following injury to the gut may help develop novel means of preventing toxicities following CRC therapy. Great expectations are placed on both preventive and regenerative medicine. On the other side of the spectrum, CRCSCs may make an important impact on translational medicine, as treatment failure is likely related to failure to eradicate tumour cells, which are able to repopulate the tumour host. Thus, how CRCSCs give rise to different treatment-resistant lineages and how the dynamics of different tumour cell populations are affected by a given type of therapy are important areas of study for future research efforts.

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