File Name: wnt pcp signaling pathway and human cancer review software.zip
- Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression.
- Role of DKK4 in Tumorigenesis and Tumor Progression
- Targeting the Wnt signalling pathway in cancer: prospects and perils
Tumor is the most public health problem. The Wnt signal pathway extensively participates in diverse progresses containing embryonic development, maintenance of homeostasis and tumor pathogenesis. A number of research of DKK1, 2, 3 have been reported, however, the effect of DKK4 on tumor process is still mysterious. A more distinct comprehension about the effect of DKK4 on tumorigenesis and tumor process will shed light on biomedical research of DKK4 and tumor research.
Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression.
Wnt signaling is a complex process and has been implicated in a large number of diseases, most notably cancer. The variety of receptors and ligands involved in Wnt signaling lead to a multitude of diverse signal transduction cascades.
The Wnt family of proteins consists of 19 known human members. Following their synthesis, these secreted Wnt proteins are modified by glycosylation and can bind to the Frizzled Fzd family of receptors.
To date, ten members of this family of receptors have been identified, all of which are seven-pass transmembrane proteins characterized by an extracellular N-terminal conserved cystein-rich domain CRD that interacts with both Wnts and other Wnt co-receptors [ 1 , 2 ]. The Fzd co-receptors, low-density lipoprotein receptor-related proteins, LRP5 and -6 are single pass transmembrane proteins and in the presence of the Fzd receptor form a co-receptor complex to which Wnts bind resulting in activation of downstream signaling [ 3 ].
The CRD domain that binds Wnt ligands was also shown to be present on the single-pass tyrosine kinase ROR2, which has also been involved in Wnt signaling [ 4 ], and other receptors for Wnts are discussed in the last section of this review. Fzd receptors are G-protein coupled receptors and downstream signaling upon Wnt binding requires heterotrimeric G proteins [ 5 ].
The activation of specific G protein subunits are dependent on the Wnt ligand subtype binding to different Fzd family members [ 6 , 7 ]. The proteins encoded by the WNT genes play a role in normal development but also in tumorigenesis [ 1 ], [ 8 ] and the inappropriate activation of the Wnt pathway results in the onset of several types of cancer [ 9 ]. In this review, we will go over the main Wnt pathways, how these pathways are modified in different types of cancers and discuss potential targets in these pathways.
This complex, often referred to as the destruction complex, also contains a protein closely related to Axin, Conductin Axin2 [ 13 ]. It is important to note that several members of the pathway can be regulated independently of Wnt signaling. Indeed, such accumulation has been detected by immunohistochemical staining in a number of human tumors including colorectal, lung, breast, cervical, skin, and liver.
This dysregulation may occur due to mutations in the various members of the signaling pathway, or to epigenetic events. Mutations in Wnt themselves are rare and although Wnt-1 was identified as a mammary oncogene in mouse transgenic studies [ 44 — 47 ], no mutations in this gene have been linked to cancers in humans. Mutations affecting downstream targets however, are quite frequent in cancer [ 48 ] [ 49 ]. The Adenomatous Polyposis Coli gene APC , one of the components of the destruction complex, was identified as a tumor suppressor protein.
Germline mutations in the gene coding for this protein is linked to an inherited form of colorectal cancer known as Familial Adenomatous Polyposis FAP , which is characterized by a large number of colorectal polyps in early adulthood [ 56 , 57 ].
Loss of APC occurs at the very initial steps of colorectal cancer and has been shown to accelerate the process of tumor initiation [ 62 ]. One of the major constituents of the destruction complex is Axin, whose concentration was shown to be the rate-limiting factor in regulating the efficiency of the destruction complex [ 25 , 65 ].
Recently, stabilization of Axin was reported in the presence of a small inhibitor of the poly ADP-ribose polymerase tankyrase [ 68 ]. Other small molecules acting on Axin protein stability have since been described[ 69 ]. To date, no inactivating mutations have been detected in human cancers [ 70 ]. However, primary breast tumors overexpress the Wnt target gene cyclin D1 [ 90 ].
This induction of cyclin D1 was shown to be due to the overexpression of Wnt ligands resulting in autocrine activation of Wnt signaling in breast cancer cells [ 91 ].
The use of monoclonal antibodies directed against these Wnts and Fzd receptors have shown promising results in vitro [ 92 ], [ 93 ] [ 94 — 98 ], but targeting the secreted ligands might be challenging due to the ubiquitous expression of the Fzd receptors and the possible activation of both canonical and non-canonical pathways. These same molecules were also shown to exhibit anti-tumor activity against multiple myeloma [ ].
In a recent study by Wei et al [ ], these antagonists were reported to inhibit human hepatocellular carcinoma cell growth with limited cytotoxicity to normal hepatocytes. This same study showed that these antagonists could slow the growth of xenografts in nude mice in preliminary studies. Moreover, both of these are inhibited by non-steroidal anti-inflammatory drugs NSAIDs which have been shown to inhibit colon tumorigenesis.
COX-2 produces eicosanoids from arachidonic acid. Treatment of mutant mice with a selective COX-2 inhibitor was shown to reduce polyp number [ ] and the treatment of FAP patients with the COX-2 inhibitor Celecoxib showed significant decrease in the number of colorectal polyps [ , ]. Activation of the Wnt pathway is regulated by secreted Wnt inhibitors Reviewed in [ 49 ]. These inhibitors affect the binding of the Wnt ligands to the receptors or co-receptors.
These Wnt antagonists include the members of the secreted frizzled related proteins sFRPs that bind to Wnt proteins directly, and the members of the Dikkopf Dkk family that bind to the Wnt co-receptors LRPs. These secreted Wnt inhibitors function to keep Wnt signaling below a certain level of activation. A number of studies have indeed described the silencing via promoter hypermethylation of the genes coding for some of the secreted Wnt antagonists in colorectal cancer [ — ].
The transcriptional inactivation of sFRPs has been detected in a number of cancers including colorectal cancer [ ], non-small-cell lung cancer [ ], breast cancer [ ], ovarian cancer [ , ]. It should be noted that overexpression of sFRPs has also been reported in some types of cancers [ — ], although the mechanisms for this overexpression or its consequence is not fully understood.
The ability of sFRPs to inhibit Wnt signaling makes them an attractive target for therapeutic use. It was shown that restoring sFRP expression in colon cancer results in a reduction in Wnt signaling, even in the case of otherwise constitutive pathway activation due to mutations in proteins downstream of receptor activation [ ].
Manipulating the expression of these proteins therefore appears to be a promising approach to downregulating Wnt signaling, especially in tumors that are characterized by mutations in the pathway, such as colorectal cancer.
Members of the Dkk family have also been shown to have an inhibitory effect on Wnt signaling, although activation of Wnt signaling, in particular by Dkk2 has been reported [ ]. It is clear that either potentiating the activity of endogenous Wnt antagonists, or designing efficacious drugs against targets of the canonical Wnt pathway could have a beneficial effect on many cancers.
However, some cancers, such as melanoma, may not fall into this category. On the other hand, non-canonical Wnt signaling can increase the metastatic potential of melanoma cells [ ]. Unlike the canonical Wnts, heretical Wnts are unable to transform mammary epithelial cells [ ] and are thought to be involved primarily in cell movement and polarity [ , ].
Receptor activation by Wnt leads to the recruitment of Dsv, resulting in the activation of Rac1 and RhoA, both of which are involved in cytoskeletton remodeling and establishment of an EMT phenotype. It is important to point out however that in elements of both pathways can be found in each, depending on the context of the tumor. LRP6 [ ] and Fzd7 [ ] seem to be critical receptors in mediating this process.
Fzd 7 has been shown to promote hepatocellular cancer and colon carcinoma, and targeting Fzd 7 can inhibit the invasion of these cells [ , ]. Rac and Rho are also well known promoters of the metastatic phenotype in many cancer types, resulting in effects on the cytoskeleton [ ].
Inhibitors of Rac and Rho therefore, would be useful in cancer therapy, and indeed this is an active field of study. Many of the inhibitors designed to target Rac and Rho actually target Ras, since this is one of the major pathways that activate these molecules.
However, small molecule inhibitors of Rac and Rho are under also development. NSC is a small molecule inhibitor of Rac that can suppress the growth and invasion of prostate cancer cells [ ]. It has been shown that in a chimeric in vivo leukemia model that is clinically similar to human disease, this inhibitor can also suppress the growth and proliferation of leukemia [ ]. C3 exotransferase has been used in vitro to inhibit both Cdc42 and Rho, but its use as a clinical agent is unknown [ ].
Cethrin, a Rho inhibitor that has been used in the clinic to treat spinal cord injuries [ ], may be of use in cancers that have Rho as an important intermediate. As with the targeting of many intermediate proteins that are necessary for many cellular processes and in many cell types, the identification and use of a specific mediator expressed in cancer, but not normal cells, could significantly decrease toxicity.
CTHRC1 is upregulated in the invasive stages of many cancers including melanoma, lung, breast, gastric, pancreatic, cervical, ovarian and thyroid cancers [ ] making it an attractive target.
Failing the development of such specific inhibitors, adjuvant therapy combining a few of the above mentioned inhibitors may have the desired effects on tumor ablation. The other well-described heretical Wnt pathway involves the release of intracellular calcium downstream of Wnt signaling Figure 3.
This results in phospho-inositol turnover in the membrane and the release of calcium from its intracellular stores. These molecules can have a cornucopia of effects on downstream signaling, that is often dependent on the cellular context. Wnt5A was shown to inhibit the activation of the canonical Wnt pathway via a number of different mechanisms including activation of CamKII [ ], and through induction of Siah, a member of the E3 ubiquitin ligase complex [ ].
Wnt5A, via CAMKII, has also been involved in the recruitment of macrophages during the inflammatory response to lipopolysaccahride [ ], and its effect on macrophage activation may also play a role in breast cancer metastasis as discussed below [ ].
For example, calcineurin is known to de-phosphorylate NFAT, causing its nuclear translocation [ ]. Data from our laboratory also show that Wnt5A inhibits the metastasis suppressor Kiss-1[ ].
Kiss-1 is known to inhibit calcineurin, thus Wnt5A may also increase calcineurin expression via the inhibition of Kiss-1, resulting in NFAT translocation.
Once in the nucleus, NFAT is capable of activating transcription programs that can contribute to cancer metastasis. This is a strong and durable interaction, but is regulated by Wnt5a signaling via Yes and Cdc42 [ ]. This is a prime example of how complex Wnt signaling can be, even when discussing the same Wnt within the same cell type! PKC is important in many cellular processes and is a critical element for Wnt5A signaling.
We and others have shown repeatedly that many of the effects of Wnt5A can be mimicked by phorbol esters, and cannot occur in the presence of PKC inhibitors [ , , ]. In neuronal cells, nerve growth factor requires Wnt5A for axonal branching and growth of neuronal cells, in a PKC-dependent manner [ ].
Wnt5A, in accordance with its different effects in the presence of different receptors, has been shown to have either a tumor suppressive or an oncogenic function, depending on the type of cancer.
Its expression is downregulated in colorectal cancer [ , ], neuroblastoma [ ], ductal breast cancer [ , ], and leukemias [ — ], and this downregulation was shown to be associated with higher tumor grade [ ].
Conversely, Wnt5A was shown to be overexpressed in gastric cancer [ ], pancreatic cancer [ ], non-small cell lung cancer [ ], and prostate cancer [ ]. Wnt5A gene expression was found to be increased in more metastatic melanoma cells [ ]and increased expression led to increased motility [ ].
In melanoma, in which Wnt5A signaling has been well studied, expression of Wnt5A is correlated with a poor prognosis [ ]. We have recently shown that the Wnt5A-mediated activation of the calcium-activated protease, calpain, results in the cleavage of the cytoskeletal protein filamin [ ]. It has been shown that Wnt5A, via ROR2, can mediate the motility of various cell types [ , ] by regulating the formation of lamellopodia and that ROR2 binding to filamin is essential for this process [ ].
Over the last decade or so we have slowly begun to unravel the intricacy of Wnt5A signaling in melanoma, and recently summarized these findings in a review [ ]. Briefly, our data indicate that Wnt5A binds to its receptor ROR2, and this binding is supported by heparan sulphate proteoglycans such as syndecan 1 and syndecan 4 [ ].
The result of this is the activation of CD44, suppression of Kiss-1, activation of Snail and Vimentin, and an epithelial to mesenchymal transition [ ]. In fact, because of this, MART1 and GP are often used as targets of immunotherapy [ ], and one can speculate that first down-regulating Wnt5A signaling might increase the efficacy of such drugs. Increases in PKC activation have been shown to increase the migration of melanoma cells, while its inhibition was able to decrease melanoma metastasis [ — ] and melanoma cell motility [ ], making PKC an attractive target, at least for melanoma metastasis.
PKC inhibitors have been investigated in the context of cancer therapy reviewed in [ ]. Again, because PKC is such an ubiquitous enzyme, finding specific, potent drugs with limited toxicity pose a problem, and targeting the source of aberrant signaling may hold the answer for future therapy. Since Wnt5A is the best-described heretical Wnt member in human cancer, it is an obvious and highly specific target.
Functional antibodies against Wnt5A have not been made available, however a study a few years ago laid the groundwork for a Wnt5A antagonist that could be used in the clinic. Foxy-5, a hexapeptide that acts as an agonist of Wnt5A was developed for use in breast cancer [ ].
Role of DKK4 in Tumorigenesis and Tumor Progression
Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e. In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases. The data were assembled to construct computationally suitable models of different WNT signaling cascades in the form of directed signaling graphs. Furthermore, these networks were integrated with microarray and RNA sequencing data to gain deeper insight into the underlying biology of gene expression differences between MCF-7 and MDA-MB breast cancer cell lines, representing weakly and highly invasive breast carcinomas, respectively. Differential genes up-regulated in the MDA-MB compared to the MCF-7 cell line were found to display enrichment in the gene set originating from the non-canonical network. Moreover, we identified and validated differentially regulated modules representing canonical and non-canonical WNT pathway components specific for the aggressive basal-like breast cancer subtype.
Targeting the Wnt signalling pathway in cancer: prospects and perils
Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity PCP pathway and inhibition of the canonical Wnt signaling branch. Editor: John D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Shaw Holly V. The Wnt pathway, involved in cancer development and progression, has for a long time been said to be undruggable, owing to its complexity and involvement in stem cell biology. This mindset has shifted in the last few years as new research and insights into the pathway mechanisms specific to tumour cells become apparent, leading to the development of multiple compounds targeting the pathway. In this review, we introduce the Wnt pathway and its connections to cancer biology and therapy resistance.
Metrics details. Over the past few years, microRNAs miRNAs have not only emerged as integral regulators of gene expression at the post-transcriptional level but also respond to signalling molecules to affect cell function s. Furthermore, the fundamental understanding of miRNA-mediated regulation of Wnt-signalling pathway and vice versa has been significantly improved by high-throughput genomics and bioinformatics technologies. Whilst, these approaches have identified a number of specific miRNA s that function as oncogenes or tumour suppressors, additional analyses will be necessary to fully unravel the links among conserved cellular signalling pathways and miRNAs and their potential associated components in cancer, thereby creating therapeutic avenues against tumours. The Wnt pathway is a highly regulated signalling pathway that controls numerous stages of animal development and tissue homeostasis.
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Единственное, что нам нужно, - осуществить такую подмену. Сьюзан сочла его план безукоризненным. Вот он - истинный Стратмор.
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