Wnt Signalling In Stem Cells And Cancer PdfBy Sven S. In and pdf 02.05.2021 at 11:21 6 min read
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- WNT Signaling in Tumors: The Way to Evade Drugs and Immunity
- Wnt signalling in stem cells and cancer
- Wnt signaling in cancer stem cells and colon cancer metastasis
- Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract
Commentary Free access
WNT Signaling in Tumors: The Way to Evade Drugs and Immunity
Glioblastoma multiforme GBM is an aggressive malignant human brain tumor 1. The prognosis for patients with GBM is unfavorable. High levels of radiation and chemotherapy, including modern cytostatic agents and targeted drugs, are unable to eliminate CSCs 7.
It is therefore, required to develop new approaches for GBM treatment and identify new molecular targets that may assist the regulation of CSCs by inhibiting their proliferative capabilities.
This suggests that similarities exist between the main mechanisms regulating the proliferative properties of these cell types. Proliferation of all types of stem cells depends on the activation of the Wnt signaling pathway In different types of malignant tumors, the activation of this pathway stimulates the proliferation of CSCs, which promotes tumor relapse and the development of therapeutic resistance 13 — A direct correlation between the aggressive nature of GBM and the activation of the Wnt signaling pathway in CSCs has previously been described Another previous study demonstrated that the suppression of the Wnt cascade decreased the heterogeneity of GBM cells This cell line is not the original U line established at the University of Uppsala, but a human GBM of unknown origin The extensive information that is available regarding this GBM cell line makes it the optimal choice for the present study.
Cells were grown in T75 culture flasks. Every 3 days, fresh growth factors were added. High-performance liquid chromatography-mass spectrometry was applied and the label-free method was used to evaluate changes in the protein expression level. Peptides were analyzed using Dionex Ultimate Dionex Corp. Mass spectrometry data were processed using MaxQuant 1.
A total of 1, proteins were identified in both samples of GBM cells. The molecular mass of the proteins was 4—3, kDa. A total of 1, proteins A total of The upregulation was observed in proteins associated with intracellular signaling pathways, including proteins involved with the extracellular matrix cell adhesion molecules, ECM receptor interaction and focal adhesion and local microenvironment tight and adherens junctions.
The majority of upregulated proteins were associated with the glycolysis pathway and Wnt signaling cascade Tables I and II. The majority of the downregulated proteins were revealed to be associated with the insulin signaling pathway and MAPK signaling pathway Table I. The absence of drugs and medical technologies for the effective elimination of CSCs in a patient's body has shifted the focus of modern research to molecular genetics.
The discovery of certain GBM isotypes based on molecular genetic analysis has provided insights into the pathogenesis of GBM; however, there remains a requirement to identify mechanisms to regulate and control CSCs 7. A number of proteins were identified to exhibit a different level of expression in CSCs, as compared with differentiated cells in GBM.
Furthermore, it was demonstrated herein that the upregulated proteins in CSCs were associated with the mechanisms of invasion, survival and proliferation. Both of these findings require further in-depth analysis. In addition to the aforementioned mechanisms, a significant change was observed in the expression of proteins associated with the Wnt signaling pathway, which was the main focus of the present study.
Embryonic cells with high levels of Wnt synthesis are known to develop into endodermal and cardiac cells, while cells with a low level of Wnt synthesis form ectoderm layers. Despite GBM being a primary neuroectodermal tumor, a number of studies have suggested its treatment resistance is associated with the activation of the Wnt pathway in CSCs This statement is supported by the presence of CD on the surface of normal neural and hematopoietic stem, endothelial progenitor and normal postnatal stem cells, and progenitor cells of other types 21 , in which the Wnt signaling pathway plays a key role 12 , Therefore, it can be hypothesized that these mechanisms are similar in GBM.
However, the upregulation of components of the Wnt signaling pathway was associated with unusual characteristics of CSCs. This finding had previously been demonstrated in GBM The present study demonstrated that the upregulation of this protein is typical in CSCs, which indicates that these cells may play a critical role in GBM biology.
Wnt signaling pathway according to the Kyoto Encyclopedia of Genes and Genomes database. This protein is crucial for the proliferation, differentiation, apoptosis, transcription, ubiquitination and cytoskeleton organization Furthermore, this protein is a component of the p53 signaling pathway that is important for GBM 7. Compared with temozolomide monotherapy, CX, a specific CK2 inhibitor, was revealed to inhibit the generation of glioma spheres in vitro and significantly increase the survival of animals with acquired GBM In addition, the expression of this protein was increased in glial tumor cells, which plays a crucial role in CSC invasion 37 , survival and proliferation The upregulation of proteins associated with the adherens junction pathway has previously been described as a characteristic of GBM cells Table III Adherens junctions signaling pathway according to the Kyoto Encyclopedia of Genes and Genomes database.
CUL1 is involved in different intracellular processes, including proliferation, differentiation and apoptosis. The hyperexpression of CUL1 was revealed to be a marker of poor prognosis for patients with stomach carcinoma, breast cancer and non-small-cell lung carcinoma.
The expression of CUL1 has been demonstrated to be significantly higher in glioma cells than in normal brain tissue The Rac2 and RhoA proteins are also components of the signaling pathway of adherens junctions Fig. Rac proteins are a subfamily of Rho small GTPases. The function of this family involves modifying the actin cytoskeleton and proliferation, and regulating key stem cell properties Rac2 is a marker of more aggressive GBM subtypes Rho GTPases belong to the Ras superfamily and these proteins, including RhoA, Rac1 and cell division control protein 42 homolog, support the transformation of the cell cytoskeleton during the epithelial-mesenchymal transition EMT.
RhoA is actively expressed in GBM cells, which promotes the migration and invasion of cancer cells. The present study revealed that the expression level of RhoA was 1. RUVBL1 plays a key role in the cell cycle, mitosis, chromatin remodeling, transcription, DNA repair, apoptosis and regulation of development of normal stem cells 48 , It also participates in oncogenic signaling pathways, including c-Myc and Wnt.
RUVBL1 regulates the activity of glucocorticosteroid and estrogen receptors in the nucleus, and is essential in choosing the optimum pharmacological scheme The inhibition of RUVBL1 activity interferes with the expression of genes responsible for the response of GBM to hypoxia and is associated with an aggressive tumor phenotype In conclusion, the present study attempted to identify molecular targets that may assist with the regulation of GBM CSC proliferation. It is essential to note that suppressing proteins of the Wnt signaling pathway are required not for producing a cytostatic and cytotoxic effect on GBM cells of the common pool, but in order to inhibit the reproductive function of CSCs and, as a result, extend the remission period.
Therefore, conceptually new methods and techniques need to be developed in order to evaluate the efficiency of suppressing these targets. Furthermore, the efficiency of the targeted therapy on extending the life expectancy of patients may not be very high, since upregulated proteins are involved in several signaling pathways.
That is why suppressing one target may have conflicting results. This approach could become a breakthrough targeted therapy for GBM. The present study was funded by the Ministry of Education and Science of the Russian Federation grant no. VS prepared and analyzed the samples, as well as performed the cell lysis, chromatography and mass spectrometry, and contributed to the bioinformatics analysis. SZ provided and performed the statistical analysis and was responsible for the mathematical process of the results.
YK and HS discussed, analyzed and interpreted the results of the study, and also worked on the manuscript. IB wrote the manuscript, proposed the study idea, designed the study, offered support with the experiments, organized the scientific team, provided scientific guidance and contributed to the bioinformatics analysis. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Crit Rev Oncog. Int J Mol Med. Front Surg. PLoS One. Cell Transplant. Prog Mol Biol Transl Sci. Kahn M: Wnt signaling in stem cells and cancer stem cells: A tale of two coactivators. Dev Biol. Genes Dis. Lab Invest. J Neuropathol Exp Neurol. Sci Transl Med. Oncol Lett. Mol Med Rep. J Pathol. Int J Biochem Cell Biol. Cancer Res.
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Wnt signalling in stem cells and cancer
Wnt signaling has emerged during evolution as a highly conserved signaling pathway that regulates tissue morphogenesis and regeneration via stem cells in various tissues of multicellular organisms 1. Therefore, activation of the Wnt pathway in CRC provides an attractive model for studying the links between tissue morphogenesis and cell adhesion and the disregulation of these processes during cancer progression. Intestinal epithelial cells display the highest turnover rate, and the entire intestinal epithelial lining in humans is replaced every 5 to 7 days The morphological separation of the stem cell compartment the crypt where the cells proliferate and the differentiated compartment villus in the intestine, and the surface epithelium in the colon, where the cells interact with the gut environment depends on a gradient of Wnt signaling. Wnt signaling is necessary for the initial potentiation of intestinal stem cells ISCs as evident from studies in neonatal transgenic mice that lost TCF4 and thus fail to develop normal proliferative crypts Both crypt homeostasis and stem cell maintenance require active Wnt signaling since conditional activation of Wnt antagonists in transgenic mice leads to the progressive loss of intestinal crypts 13 —
Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Reya and H. Reya , H. Clevers Published Biology, Medicine Nature. The canonical Wnt cascade has emerged as a critical regulator of stem cells.
Wnt signaling in cancer stem cells and colon cancer metastasis
Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. In this review, we summarize previous studies and update recent findings on canonical Wnt signaling and its components, as well as their roles in somatic stem cell homeostasis and maintenance of cancer-initiating cells. Wnt is a portmanteau of the names of the founding members of the gene family, wingless wg1 , a classical mutant in Drosophila and int1 activation of the int1 gene by viral integration leads to mammary cell transformation [ 3 — 5 ]. Wnt signaling regulates proliferation, specification, and patterning during embryonic development and regulates the balance between self-renewal and differentiation in embryonic stem cells as well as multiple somatic stem cells including hematopoietic, epidermal, neuronal, mesenchymal, and intestinal stem cells. The Wnt family in mammals comprises 19 genes encoding secreted glycoproteins that bind to Frizzled receptors and lipoprotein receptor-related protein LRP co-receptors.
Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell CSC subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance MDR, multidrug resistance and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes.
Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract
Glioblastoma multiforme GBM is an aggressive malignant human brain tumor 1. The prognosis for patients with GBM is unfavorable. High levels of radiation and chemotherapy, including modern cytostatic agents and targeted drugs, are unable to eliminate CSCs 7. It is therefore, required to develop new approaches for GBM treatment and identify new molecular targets that may assist the regulation of CSCs by inhibiting their proliferative capabilities. This suggests that similarities exist between the main mechanisms regulating the proliferative properties of these cell types.
The Wnt signaling pathway was originally uncovered as one of the prototype developmental signaling cascades in invertebrates as well as in vertebrates. The first indication that Wnt signaling also plays a role in the adult animal came from the study of the intestine of Tcf-4 Tcf7L2 knockout mice. The gastrointestinal epithelium continuously self-renews over the lifetime of an organism and is, in fact, the most rapidly self-renewing tissue of the mammalian body. Recent studies indicate that Wnt signaling plays a central role in the biology of gastrointestinal stem cells.
Subsequent studies documented similar roles for Wnt signaling in other adult stem cell compartments, such as the skin and bone marrow (Reya and Clevers ).
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Это было радостное избавление от вечного напряжения, связанного с ее служебным положением в АНБ.
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Ненадолго, - буркнул Хейл. - Не зарекайся. - Я серьезно.