The Wnt Signal Transduction Pathway in Stem Cells and Cancer Cells: Influence on Cellular Invasion

Neth, Peter; Ries, Christian; Karow, Marisa; Egea, Virginia; Ilmer, Matthias; Jochum, Marianne

doi:10.1007/s12015-007-0001-y

Cited by 108 publications

(91 citation statements)

References 113 publications

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“…This is supported by the observation that PTNtreated fAEC II had fibroblast-like F-actin distribution on the edge of the wound area. Furthermore, a canonical Wnt signaling pathway is important for the cancer cell invasion and migration (32). Our results showed that PTN activated the Wnt/␤-catenin signaling.…”

Section: Discussionmentioning

confidence: 59%

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Weng¹,

Gao

Bhaskaran

et al. 2009

Journal of Biological Chemistry

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The role of pleiotrophin in fetal lung development was investigated. We found that pleiotrophin and its receptor, proteintyrosine phosphatase receptor ␤/, were highly expressed in mesenchymal and epithelial cells of the fetal lungs, respectively. Using isolated fetal alveolar epithelial type II cells, we demonstrated that pleiotrophin promoted fetal type II cell proliferation and arrested type II cell trans-differentiation into alveolar epithelial type I cells. Pleiotrophin also increased wound healing of injured type II cell monolayer. Knockdown of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of ␤-catenin, promoted ␤-catenin translocation into the nucleus, and activated T cell factor/lymphoid enhancer factor transcription factors. Dlk1, a membrane ligand that initiates the Notch signaling pathway, was identified as a downstream target of the pleiotrophin/␤-catenin pathway by endogenous dlk1 expression, promoter assay, and chromatin immunoprecipitation. These results provide evidence that pleiotrophin regulates fetal type II cell proliferation and differentiation via integration of multiple signaling pathways including pleiotrophin, ␤-catenin, and Notch pathways.Fetal lung development is a complex biological process. Rat lung originates from the foregut endoderm as a bifurcation at embryonic day 10 (E10) and undergoes several generations of dichotomous branching morphogenesis to form a respiratory tree thereafter (1). The columnar epithelial cells differentiate into Clara cells and epithelial cells. Although surfactant protein C is detected as early as E13, fetal alveolar epithelial type II cells (fAEC II) 3 are not fully differentiated until E18 when glycogen pool-enriched cells become cuboidal and differentiate into cells containing lamellar bodies. fAEC II can further differentiate and give rise to the alveolar epithelial type I cells (AEC I).The regulation of fetal lung development includes coordinated regulation of molecular pathways as well as reciprocal interactions among mesenchymal cells, epithelial cells, and the extracellular matrix (2). Precise signals from mesenchymal cells regulate lung branching morphogenesis and lead to cell fate determination and the subsequent generation of cell type diversity in the lung epithelium. For example, mesenchymal cells secrete fibroblast growth factor 10 (3, 4). Fibroblast growth factor 10 in turn binds to its receptor, which is located on the surface of epithelial cells. The binding transduces a message to downstream signaling to regulate cell proliferation, differentiation, migration, and branching morphogenesis. Similarly, the epithelial cells also secrete signal molecules to interact with the mesenchyme. Sonic hedgehog (Shh) is growth factor expressed in the developing epithelium. Its receptor, Patched-1 (Ptc), is located on mesenchymal cells. The interaction between Shh and Ptc has been shown to be required for lung bud formation (5). Other growth factors such as pl...

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Section: Discussionmentioning

confidence: 59%

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Weng¹,

Gao

Bhaskaran

et al. 2009

Journal of Biological Chemistry

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“…Ubiquitously expressed PTK7 pseudo-kinase is an essential component of the non-canonical Wnt/PCP signaling pathway, arguably one of the most important cellular pathways in eukaryotes (46,47). At its most basic level, polarity may be considered as the generation of asymmetry within a single cell, whether the result of the asymmetry is a directed movement that leads to cellular migration or to the relocalization of specific multicellular structures.…”

Section: Discussionmentioning

confidence: 99%

Potential Relation of Aberrant Proteolysis of Human Protein Tyrosine Kinase 7 (PTK7) chuzhoi by Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) to Congenital Defects

Golubkov

Aleshin

Strongin

2011

Journal of Biological Chemistry

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Membrane PTK7 pseudo-kinase plays an essential role in planar cell polarity and the non-canonical Wnt pathway in vertebrates. Recently, a new N-ethyl-N-nitrosourea-induced mutant named chuzhoi (chz) was isolated in mice. chz embryos have severe birth defects, including a defective neural tube, defective heart and lung development, and a shortened anterior-posterior body axis. The chz mutation was mapped to the Ala-Asn-Pro tripeptide insertion into the junction region between the fifth and the sixth Ig-like domains of PTK7. Unexpectedly, chz reduced membrane localization of the PTK7 protein. We hypothesized and then proved that the chz mutation caused an insertion of an additional membrane type 1 matrix metalloproteinase cleavage site in PTK7 and that the resulting aberrant proteolysis of chz affected the migratory parameters of the cells. It is likely that aberrations in the membrane type 1 matrix metalloproteinase/PTK7 axis are detrimental to cell movements that shape the body plan and that chz represents a novel model system for increasing our understanding of the role of proteolysis in developmental pathologies, including congenital defects.About three of every 100 babies born in the United States have congenital abnormalities. Congenital abnormalities are ranked 34th of the top 50 causes of total death in the United States. Debilitating cardiovascular and nervous system defects jointly represent 40% of birth defects. The death toll of congenital abnormalities (0.58%) roughly equals that of stomach, skin, or oral cancers. Mechanistic research into birth defects is required to more efficiently contribute to prevention and correction of these disorders.The canonical, ␤-catenin-dependent and non-canonical, ␤-catenin-independent Wnt signaling pathways are conserved in eukaryotes and are critical for the diverse events in embryonic development and disease. The non-canonical Wnt/planar cell polarity (PCP) 2 signaling controls cell organization within the tissue plane (1, 2). The Wnt/PCP signaling affects the actin cytoskeleton via RhoA GTPase activation through dishevelled associated activator of morphogenesis 1 (DAAM1) and dishevelled activator of morphogenesis 2 (DAAM2). The first PCP signaling events occur at a gastrulation stage of embryogenesis. These events regulate the polarized directed cell movement to accomplish convergent extension for the anterior-posterior body axis elongation, neural tube closure, and craniofacial morphogenesis (3-6). Convergent extension failure results in a shortened anterior-posterior body axis and widened lateral axis (convergent extension phenotype), a defective neural system, and craniofacial abnormalities.Ubiquitously expressed PTK7 (also called colon carcinoma kinase-4 (CCK-4)) is a Wnt coreceptor and a regulator of PCP in vertebrates (7-13). Membrane PTK7 includes seven extracellular Ig domains, a transmembrane region, and a catalytically inert cytoplasmic tyrosine kinase (PTK) domain (8,9,11,14). PTK7 is evolutionary conserved in humans and mice and also chicken klingon (KLG...

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“…Activation of the Wnt target gene will contribute to the development of cancer in terms of proliferation, invasion and metastasis, and angiogenesis (Taketo, 2006;Neth et al, 2007). Additionally, inhibition of Wnt signalling could reduce cell proliferation and increase apoptosis in pancreatic adenocarcinoma cells (Miao et al, 2003;Pasca di Magliano et al, 2007;Nawroth et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway

et al. 2008

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Extra-pancreatic metastasis is a difficult problem for surgical intervention in pancreatic cancer. CXC chemokine receptor 4 (CXCR4) was considered to have an important role in this process. We hypothesized it may contribute to the pancreatic cancer progression through influencing canonical Wnt pathway. The purpose of this study was to examine the functional role of CXCR4 in the progression of pancreatic cancers and explore the possible mechanism. To this end, the relation between CXCR4 and clinical characteristics was analysed. shRNA against CXCR4 was applied to disrupt the SDF-1/CXCR4 signal transduction pathways in pancreatic cancer cell lines. Our results showed that overall survival in the case of patients positive for CXCR4 expression was significantly lower than that in the case of patients negative for CXCR4 expression. Notably, in vitro studies we observed that the abrogation of CXCR4 could obviously influence the pancreatic cancer cell phenotype including cell proliferation, colony formation, cell invasion and also inhibit the TOPflash activity. In addition, Wnt target genes and mesenchymal markers such as Vimentin and Slug were also inhibited in CXCR4 knockdown cells. Collectively, these data reported here demonstrate CXCR4 could modulate the canonical Wnt pathway and perhaps be a promising therapeutic target for pancreatic cancer progression.

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The Wnt Signal Transduction Pathway in Stem Cells and Cancer Cells: Influence on Cellular Invasion

Cited by 108 publications

References 113 publications

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Potential Relation of Aberrant Proteolysis of Human Protein Tyrosine Kinase 7 (PTK7) chuzhoi by Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) to Congenital Defects

Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway

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