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

Exciting new findings are emerging in the field of stem cells of normal and cancerous tissues, which may result in opportunities to develop additional strategies for therapeutic intervention in CRC. However, despite all the advances that have recently been made, it still remains somewhat unclear how increased knowledge of CRCSCs can help in developing novel therapy in the short term. If normal and malignant tissues share a common stem cell then it becomes somewhat unclear how such knowledge will benefit the development of novel therapeutic targeting, since this will not allow for selective design of targeted cancer therapy. In this scenario, it will be the acquired properties of stem cells in cancers relative to those of normal tissue stem cells and their progeny that are of most interest from the perspective of a systemic pharmacologic therapeutic approach. This may particularly be the case when one considers the data on plasticity between stem cells and their progeny. Thus, understanding how the presence of CRCSCs in tumour samples relates to prognosis and treatment responses may be the first step in facilitating clinical translation of discoveries in the CRCSC field. New advances have been made that allow for reliable detection of circulating tumour DNA and cells, and such methods could potentially be used as a method of interrogation of the population dynamics in the tumour and metastatic lesions that are being targeted. It may be of particular interest to understand how therapeutic intervention alters the cellular dynamics between CRCSCs and their progeny. One recent paper showed how knowledge about the reversion rate between differentiated radiosensitive glioblastoma (GBM) cells and radiorefractory cancer stem-like cells helped facilitate mathematical modelling of an optimal radiation dose-delivery schedule in mice carrying PDGF-driven GBMs (Leder et al., 2014). Thus, based on the preclinical data indicating that CRCSCs are treatment-refractory, understanding the population dynamics within the tumour may help in the delivery of conventional therapeutics. Further understanding of how the stem cell niche is maintained in CRC could be very helpful. Data from experimental mouse models indicate that the stem cell niche in early intestinal adenomas may be maintained by noncancerous Paneth cells (Barker et al., 2009). Paneth cells have been shown to contribute to the stem cell niche by activating EGFR, Wnt and Notch signalling in ISCs. It is generally believed that cancer cells wean themselves from extracellular signals controlling differentiation and proliferation as the disease progress. The transgenic mouse models that have been used to date have addressed the importance of ISCs in the initiation of adenomas driven by APC deletion primarily in the small intestine. Thus, such models may have limitations in demonstrating the relationship between ISCs and CRCSCs, given that the adenomas studied are nonmalignant lesions that do not metastasize to distant organs. Furthermore, premalignant or malignant lesions with oncogenic mutations of the Wnt pathway are rarely encountered in the small intestine in clinical settings. Thus, a transgenic mouse model that allows for the study of the potential conversion of ISCs to CRCSCs in the setting of metastatic disease is needed. Further development of CSC biomarkers may be important, since many of the ones currently available may not accurately and/or sufficiently selectively mark CRCSCs. Assessment of biomarkers for CRCSCs is complicated, due to the fact that candidate CRCSC populations are assessed not for their propensity to generate different tumour lineages per se, but rather for their propensity to facilitate subcutaneous xenotransplantation in an immunodeficient host. Furthermore, the functional relevance for some of the proposed CRCSCs is unknown and requires further evaluation. CRCSC biomarkers should be evaluated carefully. In order to support and validate the discovery of CRCSCs, it will likely be necessary to establish gene-expression signatures for flow-sorted cells that have been sorted for given markers. It seems unlikely that a single molecular marker would sufficiently label a CRCSC, and therefore multiple markers may have to be evaluated and combined for sensitive isolation and detection. In conclusion, we believe that the CRCSC field holds promise for the development of novel means by which to implicate a more personalized cancer therapy that ultimately may benefit CRC patients by reducing toxicity and improving the prognosis of the disease.

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