Cancer Letters

Cancer Letters

Volume 338, Issue 1, 10 September 2013, Pages 120-126
Cancer Letters

Mini-review
Regulation of intestinal cancer stem cells

https://doi.org/10.1016/j.canlet.2012.04.016Get rights and content

Abstract

Colorectal tumours harbour a sub-population of cells with stem like properties termed ‘cancer stem cells’, which are believed to ultimately drive cancer growth. This review discusses recent advances in our understanding of both normal and cancer intestinal stem cells, with emphasis on similarities and differences. Specifically we discuss the role of the Wnt, Notch and BMP pathways and their roles in both stem cell proliferation and differentiation. Furthermore we discuss the emerging role of microRNA and the influence of environmental factors such as tumour associated myofibroblasts and hypoxia on cancer stem cell regulation.

Section snippets

Normal and ’cancer’ stem cells

Normal adult tissue stem cells are a population of relatively immature cells capable of self-renewal and differentiation which are vital for tissue homeostasis. In the large intestine, the stem cell population resides at the base of the crypt and gives rise to the three major cell lineages present in the colon, namely enterocyte, endocrine and goblet cells. Intestinal stem cells are constantly renewing the intestinal epithelium so that there is a general flow of cells from the lower toward the

Regulation of CSCs: the Wnt pathway

The canonical Wnt pathway has long been recognised as an important regulator of normal intestinal stem cells [33], and more recently as a regulator of colon CSCs [34]. In the absence of sufficient Wnt signalling, cytosolic β-catenin is targeted for proteosomal degradation following casein kinase 1 (CK1) and glycogen synthase 3 (GSK3) mediated phosphorylation. Both kinases reside in a large complex with the scaffolding proteins APC and Axin-1. Extracellular Wnt ligands bind to the frizzled cell

Methylation of stem cell associated genes in cancer

Two gene signatures derived independently from either EPHB2 high or Wnt high stem cells were found to predict poor prognosis in patients [25], [32]. However rather provocatively, the Medema group showed that elevated expression of Wnt targets, including stem cell markers such as LGR5 and ASCL2, was found to be associated with good prognosis [25]. Further analysis indicated that many Wnt target genes were silenced by CpG island methylation during late development. Re-expression of silenced genes

Notch signalling

Notch is another important signalling pathway involved in regulating intestinal stem cells [63]. There are four Notch genes in mammals, which act as receptors for Jagged 1 and 2, and Delta Like (Dll) 1,3 and 4. Ligand binding to Notch results in its cleavage by γ-secretase to release the intracellular domain of Notch (NICD). NICD then translocates to the nucleus where it interacts with CBF1/RBPJ-κ to activate transcription of Notch target genes such as HES-1, -5, -7, Hey-1, Hey-2, HEYL [64].

Bone morphogenic proteins

Whilst Notch and Wnt signalling have been the main focus of research in CSC regulation, a number of other pathways have also been implicated. The Bone Morphogenic Proteins (BMPs) are multi-functional growth factors belonging to the TGFβ superfamily which have been found to influence intestinal stem cell differentiation. BMPR1 intestinal conditional knock-out mice develop multiple intestinal polyps, due to enhanced Wnt signalling and proliferation of stem cells [81]. Comparison of gene

MicroRNA and epigenetic regulation of CSCs

Some studies have begun to outline the role of microRNAs (miRNA) in regulation of CSCs. MiRNAs are small RNA molecules capable of suppressing mRNA expression. A comparison of the miRNA levels pattern of developing embryonic tissue with that of adult colorectal cancer showed a marked overlap, but not with paired non-cancerous colon tissue [83]. Members of the miR-17-92 cluster were part of this overlapping group, and inhibition of miR-17-5p reduced DLD1 cancer cell proliferation and

Influence of the tumour environment on CSCs

As well as intrinsic factors, extrinsic signalling is believed to be vital in the regulation of normal stem cells and CSCs. Normal intestinal stem cells are in close proximity to surrounding stromal cells which include myofibroblasts and smooth muscle cells, and are in close proximity to the basement membrane [86], [87]. This stromal environment is believed to form a niche that maintains the stem cell compartment [88]. In the mouse small intestine Paneth cells have been implicated in forming

Conclusions

Human colorectal cancer stem cells, as with their normal counterparts, exhibit complex regulatory mechanisms, including the Wnt, BMP and Notch pathways, and are capable of differentiation as well as self-renewal. The local tissue environment and stroma also play key roles in regulating stem cell growth in vivo, which is an area likely to be of great interest for future research. Targeting these factors will be useful for preventing tumour growth by altering the balance between self-renewal and

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