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Converging on B-Catenin Activation and Cancer Stemness

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Converging on B-Catenin Activation and Cancer Stemness View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central British Journal of Cancer (2008) 98, 1886 – 1893 & 2008 Cancer Research UK All rights reserved 0007 – 0920/08 $30.00 www.bjcancer.com Minireview Tumour–stroma interactions in colorectal cancer: converging on b-catenin activation and cancer stemness 1 1 *,1 NH Le , P Franken and R Fodde 1 Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, Erasmus MC, Rotterdam, The Netherlands Sporadic cases of colorectal cancer are primarily initiated by gene mutations in members of the canonical Wnt pathway, ultimately resulting in b-catenin stabilisation. Nevertheless, cells displaying nuclear b-catenin accumulation are nonrandomly distributed throughout the tumour mass and preferentially localise along the invasive front where parenchymal cells are in direct contact with the stromal microenvironment. Here, we discuss the putative role played by stromal cell types in regulating b-catenin intracellular accumulation in a paracrine fashion. As such, the tumour microenvironment is likely to maintain the cancer stem cell phenotype in a subset of cells, thus mediating invasion and metastasis. British Journal of Cancer (2008) 98, 1886–1893. doi:10.1038/sj.bjc.6604401 www.bjcancer.com Published online 27 May 2008 & 2008 Cancer Research UK Keywords: colorectal cancer; b-catenin; cancer stem cells; stroma; fibroblast In the intestinal tissue architecture, epithelial cells lining the axis, terminal differentiation coincides with the more restricted luminal surface are tightly regulated to ensure homeostasis. membrane-bound b-catenin localisation and its absence in the Epithelial cell renewal is fuelled by an adult stem cell compartment nucleus and cytosol (Figure 1). Recently, it has been reported that localised at the bottom of the crypt (Potten and Loeffler, 1990; the BMP antagonists, gremlin 1, gremlin 2, and chrodin-like 1, are Barker et al, 2007). As cells migrate upwards, after a transient selectively expressed by crypt-based myofibroblasts and smooth proliferative phase, the epithelium differentiates into specialised muscle cells (Kosinski et al, 2007). Moreover, Gremlin 1 was shown cell types including absorptive enterocytes, mucus secreting goblet to activate Wnt/b-catenin signalling in normal rat intestinal cells, and enteroendocrine cells. This migratory process with epithelial cells, thus indicating that stromal-derived factors concomitant differentiation is finalised when cells reach the top of regulate Wnt/b-catenin-signalling activity in the intestinal stem the crypt where they are exfoliated into the lumen upon apoptosis. cell niche. In the upper gastrointestinal tract, Paneth cells represent an Upon constitutive activation of the Wnt signalling route, exception as they move downwards while differentiating. Overall, intestinal homeostasis is disturbed, paving the way for pathogen- cell renewal, proliferation, and differentiation are coupled to esis. Indeed, the vast majority of sporadic colorectal cancer cases is positional localisation along the crypt-to-villus axis. In fact, this caused by constitutive Wnt activation due to mutations in either positional regulation of proliferation and differentiation can be the APC tumour suppressor or the b-catenin (CTNNB1) oncogene correlated to gradients in the degree of activity of several signalling (Fodde et al, 2001). Loss of APC function leads to destabilisation of pathways known to govern stemness and differentiation, including the ‘destruction complex’, a multiprotein complex encompassing Wnt/b-catenin, bone morphogenic protein (BMP), Notch, and three scaffold proteins, APC, Axin1, and Axin2 (conductin), and transforming growth factor-b (TGFb; Crosnier et al, 2006). The two kinases, glycogen synthase kinase-3b (GSK3b) and casein mesenchyme plays a complex role in the positional gradient of kinase 1 (CK1). The complex binds and phosphorylates b-catenin signalling ligand availability. Intestinal subepithelial myofibro- at serine and threonine residues, thus targeting it for ubiquitina- blasts are specialised stromal cells that form a continuous sheet tion and proteolytic degradation. In contrast, oncogenic mutations directly localised underneath the mucosa. These myofibroblasts in b-catenin render it resistant to Ser/Thr phosphorylation and contribute to epithelial cell function by providing mechanical proteolytic degradation. Upon its cytoplasmic stabilisation and support and secreting key signalling ligands. Thus, the intimate subsequent nuclear translocation, b-catenin binds to members of interaction between the parenchyme and mesenchyme ensures the TCF/LEF family of transcription factors, thus modulating proper tissue function, balancing cell renewal, and differentiation. expression of a broad range of target genes (http://www.stanford. Activation of canonical Wnt signalling characterises the base of the edu/~rnusse/pathways/targets.html). Although the presence of intestinal crypt as shown by the nuclear b-catenin localisation these initiating mutations predicts nuclear b-catenin accumulation crypt cells (Figure 1). Note that Paneth cells in the small intestine throughout the tumour mass, heterogeneous intracellular distribu- also show nuclear b-catenin accumulation as previously reported tions are observed within primary colorectal tumours and their (Van Es et al, 2005). Moving upwards along the crypt-to-villus metastases. In particular, tumour cells located at the invasive front and those migrating into the adjacent stromal tissue are earmarked *Correspondence: Dr R Fodde; E-mail: [email protected] by nuclear b-catenin accumulation (Brabletz et al, 1998, 2001; Received 7 January 2008; accepted 8 April 2008; published online 27 May Figure 1). Hence, different levels of Wnt/b-catenin-signalling 2008 activity are likely to reflect tumour heterogeneity and to underlie Tumour–stroma interactions in b-catenin-driven cancer stemness NH Le et al 1887 AB CD EF Figure 1 b-Catenin immunohistochemical staining of formalin-fixed, paraffin-embedded normal human colonic epithelia (panels A and B), and of a primary colorectal tumour (panels C and D) and a liver metastasis (panels E and F). The right panels contain magnifications ( Â 40) of specific areas from the left panels ( Â 20). The arrowheads in panels A and B indicate an epithelial cell localised at the base of the crypt with nuclear b-catenin accumulation. Both the primary colorectal tumour and liver metastasis (panels C–F) show nuclear b-catenin accumulation in cells invading the surrounding stroma, whereas other tumour cells display only membranous localisation. malignant behaviour (Gaspar and Fodde 2004; Brabletz et al, injury, when they are transiently enriched and activated (Gabbiani, 2005a). 2003). Expression of a-smooth muscle actin (a-SMA) characterises Several intrinsic (cell autonomous and/or autocrine) and these myofibroblasts and underlies contractile force tension that extrinsic (paracrine, derived from the tumour microenvironment) facilitates healing. Myofibroblasts produce a variety of growth factors may explain the observed heterogeneity of Wnt/b-catenin- factors, prostaglandins, cytokines, chemokines, and extracellular signalling activity within the tumour mass (Fodde and Brabletz, matrix components that facilitate tissue repair and survival. 2007). Here, we discuss stromal factors likely to play a role in the Myofibroblasts arise through a multitude of processes, including heterogeneous b-catenin intracellular localisation and signalling transdifferentiation of resident fibroblasts, epithelial-to-mesen- activity in tumour cells. As such, the tumour microenvironment chymal transition (EMT) of parenchymal cells, recruitment, and may drive tumour growth and even selectively support a subset differentiation of pericytes (progenitor cells localised at vascular of tumour cells, the cancer stem cells (CSCs), thus actively sinuses), and from bone marrow-derived circulating immature contributing to malignancy. fibrocytes (Desmouliere et al, 2004). Upon completion of the wound healing process, myofibroblasts revert back to their dormant state. In fact, tumorigenesis has been described as a STROMAL CELLS AFFECTING TUMOUR GROWTH, condition comparable to an open wound of chronic nature NUCLEAR b-CATENIN ACCUMULATION, AND (Dvorak, 1986). Accordingly, fibroblasts are one of the most CANCER STEMNESS abundant cell types in the stromal microenvironment associated with solid tumours (Adegboyega et al, 2002; De Wever and Mareel, As stated above, stromal regulation significantly contributes to 2003; Kalluri and Zeisberg, 2006). In response to the malignant the preservation of normal tissue architecture. Myofibroblasts, lesion within the epithelial compartment, stromal fibroblasts for example, are not only tightly associated with the intestinal become morphologically ‘activated’. Similar to the wound-healing epithelium thus ensuring homeostasis through reciprocal process, an activated response of the tumour stroma may initially interactions, but are also essential for wound healing upon tissue be triggered in an attempt to restore tissue homeostasis. However, & 2008 Cancer Research UK British Journal of Cancer (2008) 98(12), 1886 – 1893 Tumour–stroma interactions in b-catenin-driven cancer stemness NH Le et al 1888 as the tumour progresses, the microenvironment is more likely to microenvironment for pathogenic events. For instance, selective become a ‘partner in crime’ in malignancy. A subset of tumour pressure
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