Wnt/beta-catenin signaling in cancer stemness and malignant behavior

Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/beta-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling activation, resulting from mutations in genes encoding its downstream components, underlies tumorigenesis in these tissues. In the majority of sporadic colorectal cancer cases, the rate-limiting event is either loss of APC function or oncogenic beta-catenin mutations. However, although the presence of these initiating mutations would predict nuclear beta-catenin accumulation throughout the tumor mass, heterogeneous intracellular distributions of this key Wnt signaling molecule are observed within primary tumors and their metastases. In particular, tumor cells located at the invasive front and those migrating into the adjacent stromal tissues show nuclear beta-catenin staining. Hence, different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. Several intrinsic (cell-autonomous and/or autocrine) and extrinsic (paracrine, derived from the tumor microenvironment) factors may explain this heterogeneity of Wnt/beta-catenin signaling activity within the tumor mass.     

Flavonoids: potential Wnt/beta-catenin signaling modulators in cancer

Flavonoids are polyphenolic compounds found throughout the plant kingdom. They occur in every organ but are usually concentrated in leaves and flowers. During the last two decades, in vitro and in vivo studies demonstrated that flavonoids have inhibitory effects on human diseases through targeting of multiple cellular signaling components. Wnt/β-catenin signaling regulates proliferation, differentiation and fate specification in developmental stages and controls tissue homeostasis in adult life. For these reasons, this pathway has received great attention in the last years as potential pathway involved in distinct Human pathologies. In this review we discuss the emerging potential mechanisms for flavonoids on Wnt/β-catenin signaling in cancer and possible investigation strategies to understand flavonoids mode of action on this signaling pathway.     

Wnt/beta-catenin signaling in development and disease

A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades. Wnt genes encode small secreted proteins that are found in all animal genomes. Wnt signaling is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal in a number of adult tissues. Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.     

Wnt/beta-catenin signaling in adipogenesis and metabolism

Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like preadipocyte into a mature, lipid-filled adipocyte. Many of the pathways influencing this process have been identified using well-characterized preadipocyte culture systems and have subsequently been confirmed in animal models. Research conducted over the past decade has established the Wnt/beta-catenin signaling pathway as an important regulator of adipocyte differentiation. While initial reports implicated activators of Wnt/beta-catenin signaling as potent inhibitors of adipogenesis, recent investigations of mesenchymal cell fate, obesity, and type 2 diabetes highlight significant additional roles for Wnt signaling in metabolism and adipocyte biology.     

Reciprocal cross-talk between Nod2 and TAK1 signaling pathways

Mutations in the leucine-rich repeat (LRR) domain of Nod2 have been implicated in the pathogenesis of Crohn's disease, yet the function of Nod2 and regulation of the Nod2 pathway remain unclear. In this study, we determined that mitogen-activated protein kinase kinase transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) interacts with Nod2 and is required for Nod2-mediated NF-kappaB activation. The dominant negative form of TAK1 abolished muramyl dipeptide-induced NF-kappaB activation in Nod2-expressing cells. Nod2, acting in a reciprocal manner, inhibited TAK1-induced NF-kappaB activation in RICK-deficient embryonic fibroblasts. Nod2 appears to interact with TAK1 through its LRR region to exert its inhibitory effect on TAK1-induced NF-kappaB activation. Further, wild-type LRR more effectively suppressed NF-kappaB activation induced by TAK1 than LRR with a 3020insC mutation. Considered together, these findings demonstrate a critical role for TAK1 in Nod2-mediated innate immune responses and reveal a novel function for Nod2 in the regulation of the TAK1 signaling pathway.     

Wnt/beta-catenin and estrogen signaling converge in vivo

Wnt and estrogen signaling represent important regulatory pathways, each controlling a wide range of biological processes. While an increasing number of observations suggest potential convergence between these pathways, no direct evidence of their functional interaction has been reported. Using human colon and breast cancer cells, we found that estrogen receptor (ER) alpha- and beta-catenin precipitated within the same immunocomplexes, reciprocally enhanced the transactivation of cognate reporter genes, and were reciprocally recruited to cognate response elements in the promoters of endogenous target genes. Using transgenic Drosophila that ectopically expressed human ERalpha alone or together with metabolically stable beta-catenin/Armadillo mutants, we demonstrated genetic interaction between these signal transducers in vivo. Thus, we present here the first direct evidence of cross-talk between Wnt and estrogen signaling pathways via functional interaction between beta-catenin and ERalpha.     

CFTR and Wnt/beta-catenin signaling in lung development

Background  

Cystic fibrosis transmembrane conductance regulator (CFTR) was shown previously to modify stretch induced differentiation in the lung. The mechanism for CFTR modulation of lung development was examined by in utero gene transfer of either a sense or antisense construct to alter CFTR expression levels.     

Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling

Wnt/beta-catenin signaling is essential to early development. Activation of Frizzled-1 by Wnts induces nuclear accumulation of beta-catenin and activation of Lef/Tcf-dependent gene expression. Casein kinase 2 has been shown to affect Wnt/beta-catenin signaling. How casein kinase 2 exerts an influence in Wnt signaling is not clear; casein kinase 2 has been reported to be constitutively active (i.e. not regulated). Herein we show to the contrary that casein kinase 2 activity is rapidly and transiently increased in response to Wnt3a stimulation and is essential for Wnt/beta-catenin signaling. Chemical inhibition of casein kinase 2 or suppression of its expression blocks Frizzled-1 activation of Lef/Tcf-sensitive gene expression. Treatment with pertussis toxin or knock down of Galpha(q) or Galpha(o) blocks Wnt stimulation of casein kinase 2 activation, as does suppression of the phosphoprotein Dishevelled, demonstrating that casein kinase 2 is downstream of heterotrimeric G proteins and Dishevelled. Expression of a constitutively active mutant of either Galpha(q) or Galpha(o) stimulates casein kinase 2 activation and Lef/Tcf-sensitive gene expression. Thus, casein kinase 2 is shown to be regulated by Wnt3a and essential to stimulation of the Frizzled-1/beta-catenin/Lef-Tcf pathway.     

p73beta, a variant of p73, enhances Wnt/beta-catenin signaling in Saos-2 cells

The Wnt/beta-catenin pathway and p53 are very common targets for genetic alterations in colorectal cancer, and relationships between them have been reported. Here, we describe the relation between Wnt/beta-catenin signaling and the p53-related gene p73. p73, but not p53, activated a promoter containing the Tcf-binding sequence in Saos-2 cells, and the degree of activation was positively correlated with that on a p53-responsive promoter. Moreover, p73beta enhanced Wnt/beta-catenin signaling synergistically with Wnt-3a or exogenously expressed beta-catenin, unlike p53, and the enhancement was not caused by the accumulation of beta-catenin. These results show that the effects of p73 on Wnt/beta-catenin signaling differ from those of p53.     

Antagonistic regulation of convergent extension movements in Xenopus by Wnt/beta-catenin and Wnt/Ca2+ signaling

Convergent extension movements are the main driving force of Xenopus gastrulation. A fine-tuned regulation of cadherin-mediated cell-cell adhesion is thought to be required for this process. Members of the Wnt family of extracellular glycoproteins have been shown to modulate cadherin-mediated cell-cell adhesion, convergent extension movements, and cell differentiation. Here we show that endogenous Wnt/beta-catenin signaling activity is essential for convergent extension movements due to its effect on gene expression rather than on cadherins. Our data also suggest that XLEF-1 rather than XTCF-3 is required for convergent extension movements and that XLEF-1 functions in this context in the Wnt/beta-catenin pathway to regulate Xnr-3. In contrast, activation of the Wnt/Ca2+ pathway blocks convergent extension movements, with potential regulation of the Wnt/beta-catenin pathway at two different levels. PKC, activated by the Wnt/Ca2+ pathway, blocks the Wnt/beta-catenin pathway upstream of beta-catenin and phosphorylates Dishevelled. CamKII, also activated by the Wnt/Ca2+ pathway, inhibits the Wnt/beta-catenin signaling cascade downstream of beta-catenin. Thus, an opposing cross-talk of two distinct Wnt signaling cascades regulates convergent extension movements in Xenopus.     

Wnt/beta-catenin signaling and cardiogenesis: timing does matter

Recent findings in mouse and zebrafish embryos, as well as in embryonic stem cells, emphasize the critical importance of the Wnt/beta-catenin pathway in the regulation of cardiogenesis, and highlight the exquisite timing and specific cellular responses by which this signaling pathway exerts its influence. These studies clearly demonstrate that the Wnt/beta-catenin pathway plays distinct, even opposing, roles during various stages of cardiac development.     

Wnt/beta-catenin signaling and body plan formation in mouse embryos

Wnt/beta-catenin signaling plays fundamental roles in body patterning in many invertebrate and vertebrate species, by acting as a key regulator of germ layer and body axis specification. This article focuses on the roles of Wnt/beta-catenin signaling in mouse early embryos, which exhibit a unique mode of development compared to non-mammalian vertebrates. Current experimental evidence suggests that Wnt/beta-catenin signaling is not essential for patterning embryos before implantation. However, Wnt/beta-catenin signaling regulates critical developmental events after implantation, namely the patterning of visceral endoderm, the induction of primitive streak, and the formation of anterior neural ectoderm. While Wnt/beta-catenin signaling regulates the body axis formation in both mouse and frog, the mode of its action is significantly diverged between these two vertebrate species.