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Journal ArticleDOI

WNT signalling pathways as therapeutic targets in cancer

01 Jan 2013-Nature Reviews Cancer (Nature Publishing Group)-Vol. 13, Iss: 1, pp 11-26
TL;DR: This work has shown that WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis, and improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models.
Abstract: Since the initial discovery of the oncogenic activity of WNT1 in mouse mammary glands, our appreciation for the complex roles for WNT signalling pathways in cancer has increased dramatically. WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis. Although WNT signalling pathways have been difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models, thus setting the stage for clinical trials in humans.
Citations
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Journal ArticleDOI
TL;DR: It is highlighted how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state which could function as cancer stem cells, and its effects on the immunobiology of carcinomas.
Abstract: Epithelial–mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell–cell and cell–extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas. Epithelial–mesenchymal transition (EMT) is crucial for embryogenesis, wound healing and cancer development, and confers greater resistance to cancer therapies. This Review discusses the mechanisms of EMT and its roles in normal and neoplastic tissues, the contribution of cell-intrinsic signals and the microenvironment to inducing EMT, and its effects on the immunobiology of carcinomas.

1,949 citations

Journal ArticleDOI
01 Mar 2017-Oncogene
TL;DR: Current insights into novel components of Wnt pathways are reviewed and how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control are described.
Abstract: Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.

1,698 citations

Journal ArticleDOI
TL;DR: New developments in the cancer stem cell field are discussed in relationship to changing insights into how normal stem cells maintain healthy tissues and the first successes of therapies based on the CSC concept are emerging.
Abstract: The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.

1,686 citations

Journal ArticleDOI
TL;DR: The latest revelations about Cdks, cyclins and CKIs are discussed with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals.
Abstract: Cyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity. In this Review, we discuss the latest revelations about Cdks, cyclins and CKIs with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals.

1,204 citations


Cites background from "WNT signalling pathways as therapeu..."

  • ...Therefore, suppressing the Wnt pathway became an attractive route for therapeutic intervention (Anastas and Moon, 2013)....

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Journal ArticleDOI
TL;DR: This review focuses on recent developments in the understanding of the molecular actions of the core Hippo kinase cascade and discusses key open questions in the regulation and function of the Hippo pathway.
Abstract: The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell-cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

1,139 citations


Cites background from "WNT signalling pathways as therapeu..."

  • ...Mechanistically, Rho-GTPases mediate the actions ofGPCRs onYAPandTAZ....

    [...]

  • ...Gα12/13- andGαq/11-coupled GPCRs activate Rho-GTPases, which in turn inactivate LATS1/2 by a yet unknown mechanism that is dependent on F-actin assembly (Yu et al. 2012)....

    [...]

  • ...Soluble factors and G-protein-coupled receptors (GPCRs) Tissue growth requires nutrients as well as hormonal signals via autocrine, paracrine, and endocrine mechanisms....

    [...]

  • ...Amajor breakthrough in the Hippo pathway came with the discovery that diffusive molecules, such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), activate and stabilize YAP and TAZ through their GPCRs, LPA receptor (LPAR) and S1P receptor (S1PR) (Yu et al. 2012)....

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  • ...GPCRs are the largest family of the plasma membrane receptors and mediate the actions of hundreds of extracellular molecules (Lap- pano and Maggiolini 2011)....

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References
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Journal ArticleDOI
Donna M. Muzny1, Matthew N. Bainbridge1, Kyle Chang1, Huyen Dinh1  +317 moreInstitutions (24)
19 Jul 2012-Nature
TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Abstract: To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

6,883 citations

Journal ArticleDOI
18 Oct 1996-Cell
TL;DR: The authors are grateful to the members of their laboratories for their contributions to the reviewed studies and to F. Giardiello and S. Hamilton for photographs of colorectal lesions.

4,959 citations

Journal ArticleDOI
21 Mar 1997-Science
TL;DR: Results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β- catenin.
Abstract: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.

3,859 citations

Journal ArticleDOI
TL;DR: Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.
Abstract: Epithelial-mesenchymal transition is an indispensable mechanism during morphogenesis, as without mesenchymal cells, tissues and organs will never be formed. However, epithelial-cell plasticity, coupled to the transient or permanent formation of mesenchyme, goes far beyond the problem of cell-lineage segregation. Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.

3,804 citations

Journal ArticleDOI
21 Mar 1997-Science
TL;DR: Constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium.
Abstract: The adenomatous polyposis coli (APC) tumor suppressor protein binds to beta-catenin, a protein recently shown to interact with Tcf and Lef transcription factors. The gene encoding hTcf-4, a Tcf family member that is expressed in colonic epithelium, was cloned and characterized. hTcf-4 transactivates transcription only when associated with beta-catenin. Nuclei of APC-/- colon carcinoma cells were found to contain a stable beta-catenin-hTcf-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta-catenin from hTcf-4 and abrogated the transcriptional transactivation. Constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium.

3,357 citations