Wnt Signalling In Stem Cells And Cancer PdfBy Kate M. In and pdf 28.04.2021 at 13:44 10 min read
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The Wnt signaling pathway was originally uncovered as one of the prototype developmental signaling cascades in invertebrates as well as in vertebrates.
- Wnt Signaling in Normal and Malignant Stem Cells
- WNT signaling in stem cell differentiation and tumor formation
- Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract
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
Wnt Signaling in Normal and Malignant Stem Cells
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 — The intestinal crypt has long been recognized as the niche for proliferative, multipotent precursor cells of the intestine and colon, and the Wnt target gene Lgr5 , a receptor for the Wnt agonist R-spondin that enhances Wnt signaling, was identified as a marker for columnar crypt base stem cells The basic helix-loop-helix bHLH transcription factor Ascl2 is a major transcriptional regulator of genes associated with stemness in crypt cells and is a key ISC marker Similarly, the transcription factor Sox9 is also expressed by stem cells in the intestinal and colonic crypt base and is necessary for the maintenance of ISCs 21 , This points to the requirement for high Wnt signaling in the maintenance of the stem cell niche These cells display proliferative regeneration in intestinal epithelia upon cytotoxic damage and are highly sensitive to radiation-induced apoptosis 24 , Although strong Wnt signaling and the paracrine context at the crypt base are essential components that regulate the maintenance of the ISC pool, more differentiated cells retain sufficient plasticity that allows them to revert to a stem cell-like behavior under stressful conditions 29 , 30 , Since genotoxic stress and other carcinogenic perturbations may affect the stem cell pool, they may also play a key role in the development of CRC CSCs are hypothesized to constitute a small fraction of the tumor tissue.
In a role similar to that of ISCs in normal tissue, CSCs are suggested to give rise to progenitors that populate the majority of the tumor In both models, Wnt signaling is considered an important regulator. The increased frequency at which very early adenomatous polyps are observed at the top of colonic crypts far removed from the stem cell compartment has led researchers to suggest that neoplastic transformation in CRC is initiated from differentiated cells On the other hand, immunohistochemical studies of early sporadic colorectal adenomas have shown adenomatous lesions near the crypt base The suppression of APC by this method resulted in intestinal and colon cancer development in mice.
Restoration of APC expression in these tumors resulted in the reversal of tumorigenic lesions and the complete reconstitution of a normal stem cell compartment, even in mice harboring oncogenic Kras and p53 These invasive edge-localized cells were shown to preferentially express Wnt target genes that confer invasive-metastatic capacity when expressed in human CRC cells 44 — Vermeulen et al.
The Wnt high cells formed more tumors in mice with fewer injected cells compared with Wnt low cells. This heterogeneity in Wnt signaling was maintained in the tumors formed in mice that also expressed several ISC markers, including Lgr5 and Ascl2 The importance of Wnt signaling in the maintenance of the CSC pool and in driving CRC progression is also highlighted in a study in which conditional activation of the Wnt antagonist HoxA5 suppressed tumor growth and metastatic progression by repressing stemness properties Lgr5, a target gene of Wnt signaling, is a well-established ISC marker Recent studies attempting to define an ISC gene signature in CRC tissue repeatedly detected Lgr5 as a key component in such signatures 49 — The presence of Lgr5 on the surface of cells is sufficient for successful isolation of the CSC fraction from CRC tissue, and similar to its role in the normal intestine, Lgr5 defines the undifferentiated stem cell state in CSCs.
CRC cells with high Lgr5 expression had enhanced ability to clonally expand and give rise to colonies in vitro , whereas suppression of Lgr5 expression results in the loss of their ability to form colonies An ISC gene signature derived from EphB2 high columnar crypt base cells was suggested as a powerful predicting tool of human CRC progression and disease relapse Tumors with high levels of Lgr5-ISC signature genes were more aggressive and metastatic and also displayed an increased tendency to relapse in patients with CRC However, other studies have defined a non-Wnt-induced CSC gene list that does not include Lgr5 or other well-established Wnt-target genes.
In a study on disease recurrence in CRC patients who went through curative surgery, a reverse correlation between Wnt-target genes Lgr5 , Ascl2 , Axin2 , Dkk1 , and Apcdd1 levels and disease recurrence was found, suggesting that elevated expression of Wnt-target genes is associated with good prognosis Based on studies with CRC cell lines, these Wnt-target genes were silenced by CpG island methylation, and once methylation was inhibited, these cells lost their ability to generate colonies in vitro.
These cells apparently go through an epithelial-to-mesenchymal transition EMT , thus making them more motile and invasive, implying a role for the Wnt-induced CSCs in the propagation of metastasis. EMT has been suggested for some time as a key mechanism governing the generation of CSCs, especially as revealed by studies using breast cancer cell lines In CRC, the EMT program influences a variety of malignant phenotypes associated with metastasis, including the generation of CSCs, tumor budding, circulating tumor cells, and drug resistance The role of EMT in epithelial cancer, however, is still incompletely understood.
Recent reports on lung and pancreatic cancer found that although EMT affects chemoresistance, it is not required for metastasis 57 , Since CSCs can both self-renew and differentiate, such cells can better adjust to the changes involved in the various stages of cancer metastasis The involvement of CSCs derived by activation of Wnt signaling in the later stages of cancer progression was suggested in a study showing that Lgr5 expression correlated with the malignant potential of CRC tumors and cell lines Tumors displaying increased levels of Lgr5 were of higher stage and were more invasive and formed more lymph node metastases According to this model, the inherent plasticity of CSCs is employed during the advanced stages of cancer progression that require the acquisition of invasive properties and migration through the blood and lymph vessels to distant organs.
Newly formed metastatic tumors were shown to have a high genomic and proteomic similarity to the primary tumors from which they were derived, suggesting that after colonization MCSCs revert to their initial phenotype A study comparing gene expression from primary CRC tissue and liver metastatic foci of the same patients found that the expression of Ascl2 an ISC marker and Wnt target gene is upregulated in the metastatic tumors together with several other Wnt-induced ISC markers, including Lgr5 , EphB3 , Ets2 , and Sox9 Smoc2 expression was preferentially increased at the invasive edge of CRC tumors, and Smoc2 exclusively localized at the bottom of colonic crypts in the normal colonic epithelium Moreover, L1-induced metastatic CRC cell lines lost their metastatic potential when Smoc2 was silenced SMAD4 mutations were shown to account for the shift in CRC tumor phenotype from the large adenoma to the adenocarcinoma stage 72 , This is achieved by abrogating Wnt-triggered BMP4 expression in stem cells derived from colorectal adenoma that is apparently required for stem cell self-renewal in colon adenoma Msi1 can trigger the activation of Wnt and Notch signaling by a positive feedback regulation in ISCs, a regulatory loop recapitulated during CRC development Thus, together, these results suggest that the increase in Wnt signaling, even in more differentiated CRC cells, promotes the acquisition of a phenotype resembling that of ISCs by reconstituting a signaling environment that supports dedifferentiation.
A common concept in cancer development suggests that tumors arise from proliferation and survival of a clonal subpopulation of stem cells within the tumor. However, studies with CRC indicate that tumors may arise from several different parent cells, each contributing a distinct lesion and thus generating polyclonal tumors Polyclonal adenomas were also observed in mice with a chimeric loss in APC in the intestinal epithelium Conditional deletion of APC in stem cells labeled with a fluorescence reporter for Lgr5 triggered the development of adenomas from different cell clones within the intestinal tract Although a stem cell hierarchy is supposed to exist in the CRC tissue, the high plasticity also means that the expression of ISC signature genes may be heterogeneous and thus cancer cells not originating from ISCs may also express ISC signature genes to some extent.
The contradictory reports regarding the association of Lgr5 with various stages of CRC progression 49 , 50 , 53 , 54 , 90 — 92 could be explained by the heterogeneity among the cells of the CRC tissue, as related to the expression of stem cell markers.
Given that some stem cell markers are not dependent on Wnt signaling, further studies are required to determine the functional relevance of the many genes identified as stem cell signature genes in both normal and CRC tissue.
Determining their roles in CRC not only will provide a better understanding of their function in intestinal homeostasis but will provide novel markers for targeting CRC. Using expression profiles for multiple stem cell markers in tandem increases the successful prediction of prognosis and outcome in CRC Further studies of the stem cell niche and the molecules controlling self-renewal will provide a better definition of markers for the stem cell compartment.
Current paradigms propose that treatments against cancer that fail to eradicate the CSC population will have little success in preventing future relapses of the disease. If correct, this hypothesis calls for additional research aiming to identify and understand the role of the subpopulations of CSCs in cancer development and for their more effective targeting.
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Home Browse Wnt signaling in cancer stem cells and colon cancer metastasis. ALL Metrics. Get PDF. Get XML. How to cite this article. NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details. Wnt signaling in cancer stem cells and colon cancer metastasis [version 1; peer review: 3 approved].
The Wnt pathway is a key regulator of both the early and the later, more invasive, stages of CRC development. In the normal intestine and colon, Wnt signaling controls the homeostasis of intestinal stem cells ISCs that fuel, via proliferation, upward movement of progeny cells from the crypt bottom toward the villus and differentiation into all cell types that constitute the intestine. Studies in recent years suggested that cancer stem cells CSCs , similar to ISCs of the crypts, consist of a small subpopulation of the tumor and are responsible for the initiation and progression of the disease.
Although various ISC signature genes were also identified as CRC markers and some of these genes were even demonstrated to have a direct functional role in CRC development, the origin of CSCs and their contribution to cancer progression is still debated.
Corresponding Author s. Avri Ben-Ze'ev avri. Introduction 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. Wnt signaling in intestinal stem cell homeostasis Intestinal epithelial cells display the highest turnover rate, and the entire intestinal epithelial lining in humans is replaced every 5 to 7 days Cancer stem cells and Wnt signaling in colorectal cancer CSCs are hypothesized to constitute a small fraction of the tumor tissue.
Lgr5 as a Wnt-induced cancer stem cell marker Lgr5, a target gene of Wnt signaling, is a well-established ISC marker Competing interests The authors declare that they have no competing interests.
F recommended References 1. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. J Clin Invest.
WNT signaling in stem cell differentiation and tumor formation
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.
PDF | The Wnt signaling pathway was originally uncovered as one of the prototype developmental signaling cascades in invertebrates as well.
Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract
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Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development.
ГЛАВА 53 Токуген Нуматака лежал на массажном столе в своем кабинете на верхнем этаже. Личная массажистка разминала затекшие мышцы его шеи. Погрузив ладони в складки жира на плечах шефа, она медленно двигалась вниз, к полотенцу, прикрывавшему нижнюю часть его спины. Ее руки спускались все ниже, забираясь под полотенце.
Но она не была прижата к боку, как раньше, и его тело уже не опутывали веревки. Теперь рука была закинута за голову, следовательно, Хейл лежал на спине. Неужели высвободился.
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Сьюзан проигнорировала его вопрос и села за свой терминал. Ввела личный код, и экран тотчас ожил, показав, что Следопыт работает, хотя и не дал пока никакой информации о Северной Дакоте. Черт возьми, - подумала Сьюзан. - Почему же так долго.
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- Говорит Лиланд Фонтейн. Слушайте меня внимательно… ГЛАВА 112 - Надеюсь, вы знаете, что делаете, директор, - холодно сказал Джабба. - Мы упускаем последнюю возможность вырубить питание.
Дэвид прислал его после какой-то мелкой размолвки. Несколько месяцев она добивалась, чтобы он объяснил, что это значит, но Дэвид молчал. Моя любовь без воска.
Стратмор убил Чатрукьяна. Хейл, видимо, не догадывается, что она видела его внизу.