Regulation of CRCSCs

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

Stem cell signalling pathways

Dysregulation of the pathways that govern ISCs is an important feature of CRC (Figure 9.2). Mutations in TGF-β and Smad4, critical regulators of stem cell maintenance, are commonly observed in CRC (Joudeh et al., 2013). APC tumour suppressor loss, Wnt pathway activation and β-catenin mutation result in an abnormal expansion of intestinal crypt stem cells and loss of crypt architecture, ultimately resulting in CRC (Zhu et al., 2009). Notch signalling regulates self-renewal and differentiation in the intestinal epithelium and is elevated in CRCSCs. Notch signalling is important for CRCSC maintenance and resistance to apoptosis (Sikandar et al., 2010). Similarly, the Hedgehog (Hh) – Gli signalling pathway that governs differentiation in the normal intestine is also activated in CRC and is important for CRCSC self-renewal (Varnat et al., 2009). Thus, dysregulated stem cell signalling pathways in CRC may serve as important drug targets in CRCSCs.

Other CRC signalling pathways

Several other signalling pathways involved in CRC also regulate CRCSCs (Figure 9.2). The tumour-suppressor p53 protects normal cells in response to various stresses by inducing cell-cycle arrest, senescence or apoptosis. Recent evidence suggests that an important aspect of the tumour-suppressive role of p53 is its regulation of stem cell differentiation and self-renewal. Loss of p53 correlates with poorly differentiated tumours in CRC. It results in CRCSC enrichment, while p53 pathway restoration depletes CRCSCs (Prabhu et al., 2012).

As mentioned in Section, APC loss is an important initiating event in CRC. The mechanisms involved in ISC expansion and hyperproliferation upon APC loss were recently delineated. RAC1 GTPase-mediated NF-?B activation and reactive oxygen species (ROS) production are involved in Lgr5 stem cell expansion and hyperproliferation, leading to adenoma formation (Myant et al., 2013).

CRCSCs have the capacity to differentiate and give rise to multiple different cell types within CRC tumours, including goblet-like, enterocyte-like and neuroendocrine (NE)-like cells. The PI3K pathway plays an important role in CRCSC multilineage differentiation, as PI3K inhibition shifts the process to a more enterocyte-like differentiation (Vermeulen et al., 2008).

The inhibitor-of-DNA-binding-protein (ID) family regulates the self-renewal of embryonic stem cells, as well as adult tissue stem cells, and ID proteins are overexpressed in CRC. ID1 and ID3 regulate CRCSCs via p21. ID1 and ID3 knockdown results in loss of CRCSC-mediated tumour initiation and self-renewal, decreased p21 levels, increased DNA damage accumulation and increased sensitivity to oxaliplatin (O’Brien et al., 2012).

Tumour microenvironment

ISCs receive signals of self-renewal and differentiation, such as Wnt, Notch and bone morphogenetic protein, from the surrounding stroma and niche cells (Joudeh et al., 2013). Similarly, CRCSCs rely on signals from the surrounding hypoxic tumour microenvironment and cancer-associated endothelial cells and fibroblasts for maintenance of stemness and initiation of differentiation or proliferation. Myofibroblast-secreted HGF is important to enhancing Wnt-β-catenin signalling in CRC cells and maintaining a CRCSC phenotype. Myofibroblastsecreted factors also induce a CRCSC phenotype in differentiated CRC cells, via Wnt-β-catenin signalling (Vermeulen et al., 2010). CRC-associated endothelial cells secrete a soluble form of Jagged-1 that can activate Notch signalling in CRC cells. The soluble Jagged-1 arises via ADAM17 protease, promoting a CRCSC phenotype, chemotherapy resistance and metastasis (Lu et al., 2013). The hypoxic tumour microenvironment can also help maintain the CRCSC phenotype via Hif1a, Bmi1 and Notch1. Interestingly, this effect of hypoxia on CRC cells is reversible (Yeung et al., 2011).


In cancer, miRs are frequently dysregulated. They regulate target gene expression and cell fate by inhibiting mRNA translation or marking mRNAs for degradation. Recent studies have investigated the role of miRs in CRCSC regulation. The p53 target miR-34a prevents CRCSC self-renewal by inhibiting Notch signalling. It regulates Notch1 levels in a bimodal manner, determines whether CRCSCs undergo self-renewal or differentiation and regulates symmetric versus asymmetric CRCSC division (Bu et al., 2013).

The transcription factor Snail, a key EMT mediator, increases miR-146a, which stabilizes Wnt activity and CRCSC symmetrical division, fuelling tumour growth and cetuximab resistance (Hwang et al., 2014). Micro-RNAs are usually transcribed as long precursors and are converted into mature miRs via DICER1 activity. Loss of DICER1 function results in enrichment of CRCSCs, an EMT phenotype and increased metastasis. The effects of impaired DICER1 are mediated by the resulting loss of several miRs, such as miR-34a and miR-200 family members (Iliou et al., 2014). Loss of miR-200c elevates CRCSCs, EMT and metastasis (Lu et al., 2014).

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