Aberrant signaling pathways in medulloblastomas: a stem cell connection

Rodini, Carolina Oliveira; Suzuki, Daniela Emi; Nakahata, Adriana Miti; Pereira, Márcia Cristina Leite; Janjoppi, Luciana; Toledo, Sílvia Regina Caminada de; Okamoto, Oswaldo Keith

doi:10.1590/s0004-282x2010000600021

Cited by 15 publications

(19 citation statements)

References 56 publications

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“…S7). This is in agreement with results previously described in human and mouse models of MDB and mouse models of MDB (Aref et al, 2013; Guessous et al, 2008; Rodini et al, 2010). Smad3/TGFβ activity continued to be sustained till 30 dpf with a very slow decrease.…”

Section: Resultssupporting

confidence: 93%

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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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Section: Resultssupporting

confidence: 93%

“…Significant increase in stat1b and TGFβ signaling and a strong reduction in p53 expression (supplementary material Fig. S9) were compatible with hyperproliferation of KRAS G12D -positive cells responsible for MDB progression (Rodini et al, 2010). …”

Section: Resultsmentioning

confidence: 87%

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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“…As well known in the literature, in fact, developmental cascades, when deregulated, acquire oncogenic effect. Neuronal development and tumorigenesis rely on cell communication via identical signaling pathways, resulting in a complex signaling network that creates a breeding ground for tumor-initiating events (Peifer and Polakis, 2000; Schwartz and Ginsberg, 2002; Clark et al, 2007; Katoh, 2007; Neth et al, 2007; Guo and Wang, 2009; Rodini et al, 2010; Mimeault and Batra, 2011; Roussel and Hatten, 2011; Akhurst and Hata, 2012; Manoranjan et al, 2012). …”

Section: Resultsmentioning

confidence: 99%

“…After this intense proliferative phase, around the second postnatal week in mouse, GPCs exit the cell cycle and migrate radially to the IGL, along the Bergmann glia. During this inward migration, differentiation of post-mitotic GPCs takes place, allowing the mature granule neurons to expand the IGL, where they extend dendrites (Dyer, 2004; Rodini et al, 2010; Wang and Wechsler-Reya, 2014). As a consequence of a hyperactivation of the Shh pathway occurring in the Ptch1 +/− MB mouse model, the prolonged mitotic activity of GCPs makes them potential targets for transforming insults, leading to MB (Wang and Zoghbi, 2001).…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Gentile¹,

Ceccarelli²,

Micheli³

et al. 2016

Front. Pharmacol.

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We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/−/Tis21KO). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+/−/Tis21 wild-type vs. Ptch1+/−/Tis21 knockout), among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

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“…Outro exemplo seria o meduloblastoma, tumor que atinge o cerebelo ainda na infância e que é altamente maligno. Essa neoplasia parece se originar de precursores indiferenciados de neurônios granulares do cerebelo, que se proliferam indiscriminadamente após mutações em vias sinalizatórias como Shh, Notch e WNT 29 . Dessa forma, torna-se evidente o papel central que o processo de diferenciação das CTNs em células maduras executa na patogênese dessas doenças.…”

Section: Estudos Já Notificaram Uma Hiper Ativação Dessa Via Emunclassified

Perspectivas de terapia celular em neurologia

Onuchic

Batista

Lepski³

2015

Rev. Med. (São Paulo)

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RESUMO:Neste artigo de revisão, buscamos ressaltar alguns dos avanços mais recentes na pesquisa sobre células-tronco em neurologia. Além disso, buscamos demonstrar a direta associação entre seu funcionamento e mecanismos de replicação, diferenciação e maturação, além da terapêutica celular de algumas doenças neurológicas. Abordamos a provável associação entre essas células indiferenciadas e a origem de alguns tumores malignos do SNC, bem como os potenciais terapêuticos que o transplante das mesmas tem na medicina neurológica regenerativa. Por fim, concluímos que o entendimento e a pesquisa sobre esses mecanismos podem abrir portas para abordagens mais diretas e eficazes de diversas doenças atualmente incuráveis do sistema nervoso.Descritores: Terapia baseada em transplante de células e tecidos; Medicina regenerativa; Células-tronco; Pesquisa com células-tronco; Doenças do sistema nervoso/diagnóstico; Neurologia. ABSTRACT:In this review, we sought to highlight some of the latest advances in stem-cell research in neurology. In addition, we demonstrated the direct association between its functioning and replication mechanisms, differentiation and maturation, and also the cell therapy involved in some neurological diseases. We discussed the possible association between these undifferentiated cells and the source of some malignant tumors of the CNS, as well as the therapeutic potential of transplanting these cells in neurologic regenerative medicine. Finally, we conclude that the understanding and research on these mechanisms may lead the way to more direct and effective approaches of several currently incurable diseases of the nervous system. Keywords:Cell-and tissue-based therapy; Regenerative medicine; Stem cells; Steam cell research; Nervous system diseases/diagnosis; Neurology. INTRODUÇÃOO uso de células-tronco representa uma alternativa promissora no futuro da medicina regenerativa, incluindo as doenças neurológicas, nas quais a perda de neurônios muitas vezes acarreta danos e sintomas irreversíveis ao paciente. Essas células possuem a capacidade tanto de se auto-renovar, gerando descendentes iguais, quanto de se diferenciar em células adultas, maduras e especializadas, participando, dessa forma, do crescimento, reparação e manutenção da homeostasia nos diferentes tecidos do organismo 1 .De acordo com sua origem, as células-tronco podem ser divididas em 3 subgrupos: embrionárias, que provêm da camada celular interna do blastocisto; fetais, que são oriundas de partes do feto; e adultas, que são extraídas de tecidos adultos já desenvolvidos. Em relação ao seu grau de plasticidade -ou seja, o seu potencial de diferenciação em diferentes tecidos -as células-tronco podem ser classificadas em totipotentes, pluripotentes e multipotentes. As células totipotentes são as mais indiferenciadas, e são encontradas no embrião nas primeiras fases de divisão. São

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Aberrant signaling pathways in medulloblastomas: a stem cell connection

Cited by 15 publications

References 56 publications

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

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

Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma Shh-Type Development

Perspectivas de terapia celular em neurologia

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