Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome

Abstract

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.

Keywords: cancer stem cells; colorectal carcinoma; feedback loop; miRNAs; regulatory network; signaling pathways.

Figure 1

Origin of colorectal cancer stem cells (CCSC) and their role in tumor progression. Colorectal cancer (CRC) cells may originate from intestinal stem cells (ISCs), cells in transit, and terminally differentiated cells gaining a transforming mutation. A single mutation in an ISC could originate a CCSC; at least one transforming, and one de-differentiating mutation would be needed to transform a transit-amplifying (TA) or differentiated cell into a CCSC.

Figure 2

Overview of feedback loops between signaling pathways involved in CRC pathogenesis and controlling stem cell behavior through regulation of β-catenin, a key downstream convergent component. (A) c-MET activation induces AKT and GSK3β phosphorylation leading to LRP5/6 phosphorylation and β-catenin stabilization; deregulation of BMP signaling stabilizes β-catenin by downregulation of SMAD4 and PTEN phosphorylation; Hippo signaling repression stabilizes β-catenin reducing the TAZ-DVL complex in the cytoplasm, while the increasing of TAZ/YAP complex in the nucleus cooperates with β-catenin. (B) RSPOs induce RNF43/ZNRF3 ubiquitination improving WNT canonical and non-canonical signaling. (C) The interactions between Notch and WNT signaling improve Notch activity, GSK3β phosphorylates NICD-1 favoring localization in the nucleus, CaMKII induces phosphorylation of SMRT increasing promoter activity of Notch-responsive genes; the crosstalk between Hedgehog and WNT signaling includes Gli-3 phosphorylation by GSK3β/CK1 blocking Gli-1 activity, SFRP-1 interacts with Gli-1 and β-catenin to control their nuclear–cytoplasmic distributions.

Figure 3

Main miRNAs regulating colorectal cancer stem cell features. The figure shows miRNAs-mRNA interactions that may reduce or promote the development and features of CCSC, such as cell cycle, self-renewal and differentiation, EMT process, and drug resistance linked to the initiation and progression of CRC. MiR-21 is an oncomiR that promotes CCSCs development by interacting with PTEN and TGFβR2. A regulatory loop has been identified between miR-16 and TP53, its deregulation in CCR favors development of CCSCs.