Role of Sonic hedgehog signaling and the expression of its components in human embryonic stem cells

Wu, Selena Meiyun; Choo, Andre; Yap, Miranda G.S.; Chan, Ken Kwok‐Keung

doi:10.1016/j.scr.2009.09.002

Cited by 44 publications

(41 citation statements)

References 48 publications

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“…Activation of the SHH pathway drives the development of neural crest stem cells and the sympathetic nervous system (Wu et al, 2010). Thus, it is not surprising that dysregulation of the SHH pathway correlates with the central nervous system tumorigenesis (Dahmane et al, 2001).…”

Section: Gscs and Their Characteristicsmentioning

confidence: 99%

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

et al. 2016

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Glioblastoma multiforme (GBM), grade IV astrocytoma, is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. Recent studies showed that GSCs reside in particular tumor niches that are necessary to support their behavior. To successfully eradicate GBM growth and recurrence, new strategies selectively targeting GSCs and/or their microenvironmental niche should be designed. In this regard, here we focus on elucidating the molecular mechanisms that govern these GSC properties and on understanding the mechanism of the microenvironmental signals within the tumor mass. Moreover, to overcome the blood–brain barrier, which represents a critical limitation of GBM treatments, a new drug delivery system should be developed. Nanoparticles can be easily modified by different methods to facilitate delivery efficiency of chemotherapeutics, to enhance the accumulation within the tumors, and to promote the capacity for targeting the GSCs. Therefore, nanotechnology has become the most promising approach to GSC-targeting therapy. Additionally, we discussed the future of nanotechnology-based targeted therapy and point out the disadvantages that should be overcome.

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Section: Gscs and Their Characteristicsmentioning

confidence: 99%

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

et al. 2016

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“…In pancreatic adenocarcinoma of both acinar and ductal origins most pathways, including Sonic Hedgehog (Shh), Wnt, Notch and transforming growth factor β (TGFβ) signaling, have been shown to be dysregulated (Bailey and Leach, 2012). During embryonic development, Shh plays a major role in stem-cell proliferation (Wu et al, 2010); the Wnt pathway is involved in cell proliferation and differentiation (Yang, 2012); Notch is responsible for stem-cell maintenance (Kwon et al, 2012); and TGFβ controls cell and tissue homeostasis, favoring cell apoptosis by cross-talking with other pathways such as p53 (Elston and Inman, 2012). TGFβ is also involved in tissue morphogenesis, in cooperation with Wnt pathway, by controlling epithelial-to-mesenchymal transition (EMT) and cell migration (Jing et al, 2011; Zhou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Schiavone

Rampazzo

Casari

et al. 2014

Disease Models &Amp; Mechanisms

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Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRASG12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRASG12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRASG12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRASG12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRASG12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

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“…In the squamous cell carcinoma of the lungs, protein kinase CΙ (PKCΙ) was found to phosphorylate Sox2 and recruit it to the Hh acyltransferase ( HHAT ) promoter for Hh ligand production and maintenance of a stem-like phenotype [349]. Although study showed minimal role of SHh pathway in maintaining pluripotency and regulating the proliferation of undifferentiated hESCs, Gli-responsive luciferase assay and target genes Ptch1 and Gli1 expression during differentiation with retinoic acid revealed that the SHh signaling pathway is highly activated [93]. Besides, addition of exogenous SHh to differentiating hESC as embryoid bodies increases the expression of neuroectodermal markers Nestin, SOX1, MAP2, MSI1, and MSX1, suggesting that SHh signaling is important during hESC differentiation toward the neuroectodermal lineage [93].…”

Section: Specific Protein Kinases and Associated Signaling Pathwaymentioning

confidence: 99%

“…Although study showed minimal role of SHh pathway in maintaining pluripotency and regulating the proliferation of undifferentiated hESCs, Gli-responsive luciferase assay and target genes Ptch1 and Gli1 expression during differentiation with retinoic acid revealed that the SHh signaling pathway is highly activated [93]. Besides, addition of exogenous SHh to differentiating hESC as embryoid bodies increases the expression of neuroectodermal markers Nestin, SOX1, MAP2, MSI1, and MSX1, suggesting that SHh signaling is important during hESC differentiation toward the neuroectodermal lineage [93]. This comes in line with a previous report [350] that implicates the Hh pathway in a core developmental signaling network repressive for pluripotency, as revealed by a ChIP-chip dataset that regulates Yamanaka factors in iPSCs.…”

Section: Specific Protein Kinases and Associated Signaling Pathwaymentioning

confidence: 99%

“…The JAK/STAT [88] and Src pathways [89] have also a significant impact on this process. Although not extensively investigated, signaling cascades through Aurora kinases [90], Bcr-Abl [91] and Hedgehog pathway [92, 93] or pathways influenced by neurotrophins (NTs) and tyrosine kinase receptors (TKRs) [94], have been implicated in the maintenance of pluripotency, whereas others, including the stem cell factor (SCF) / Kit pathway [95, 96], Tie2 [97] and Flk1 [98], are mostly involved in the lineage commitment of pre-differentiated PSCs. Protein kinase C (PKC) seems to be a requirement for the differentiation of hESCs [99, 100].…”

Section: General Introduction To Protein Kinases and Pluripotencymentioning

confidence: 99%

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Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

Shoni

Lui

Vavvas

et al. 2014

CSCR

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Protein kinases (PKs) mediate the reversible conversion of substrate proteins to phosphorylated forms, a key process in controlling intracellular signaling transduction cascades. Pluripotency is, among others, characterized by specifically expressed PKs forming a highly interconnected regulatory network that culminates in a finely-balanced molecular switch. Current high-throughput phosphoproteomic approaches have shed light on the specific regulatory PKs and their function in controlling pluripotent states. Pluripotent cell-derived endothelial and hematopoietic developments represent an example of the importance of pluripotency in cancer therapeutics and organ regeneration. This review attempts to provide the hitherto known kinome profile and the individual characterization of PK-related pathways that regulate pluripotency. Elucidating the underlying intrinsic and extrinsic signals may improve our understanding of the different pluripotent states, the maintenance or induction of pluripotency, and the ability to tailor lineage differentiation, with a particular focus on endothelial cell differentiation for anti-cancer treatment, cell-based tissue engineering, and regenerative medicine strategies.

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Role of Sonic hedgehog signaling and the expression of its components in human embryonic stem cells

Cited by 44 publications

References 48 publications

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Protein Kinases and Associated Pathways in Pluripotent State and Lineage Differentiation

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