Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells

Main, Heather; Lee, Kian Leong; Yang, Henry; Haapa-Paananen, Saija; Edgren, Henrik; Jin, Shaobo; Sahlgren, Cecilia; Kallioniemi, Olli; Poellinger, Lorenz; Lim, Bing; Lendahl, Urban

doi:10.1016/j.yexcr.2009.12.012

Cited by 30 publications

(30 citation statements)

References 57 publications

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“…[18][19][20] Therefore, we examined Notch signaling in fetal and adult CSps under physiological oxygen conditions (5% O 2 ). CMPC-CSps exhibited an increase in the RNA expression of all Notch components [ Fig.…”

Section: Notch Signaling Enhancement In Cpc Spheroids Is Increased Bymentioning

confidence: 99%

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

et al. 2017

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Cardiac progenitor cells (CPCs) are a promising candidate for cardiac regeneration, and the interaction between CPCs and their microenvironment can influence their regenerative response. Notch signaling plays a key role in cell fate decisions in the developing and adult heart. Here, we investigated the effect of three-dimensional (3D) spheroid culture, as a model of the 3D microenvironment, on Notch in fetal and adult human CPCs, under room air (20%) and physiological (5%) oxygen tension. Notch signaling is enhanced in 3D spheroids; spheroid culture under 5% O 2 further increases Notch signaling enhancement, and might ultimately improve the regenerative potential of CPCs.

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Section: Notch Signaling Enhancement In Cpc Spheroids Is Increased Bymentioning

confidence: 99%

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

et al. 2017

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“…Cooperative cross-talks between hypoxia and Notch signaling have previously been documented in mouse embryonic stem cells and progenitor cells [19,20,21,22], human breast cancer pathogenesis [17,23]; and maintenance of stem cells in different tumors [7,24,25,26,27,28,29,30,31]. Few studies have also addressed the altered expression of Notch signaling genes in surgically resected GBM [18,32,33] and their interaction with hypoxia in human [34,35] and rat glioma cell lines [36].…”

Section: Introductionmentioning

confidence: 99%

A Combined Gene Signature of Hypoxia and Notch Pathway in Human Glioblastoma and Its Prognostic Relevance

et al. 2015

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Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor—clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

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“…Several mechanisms have been proposed including direct icN1 stabilization by interaction with HIF proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). As of yet, little attention has been given to Notch ligand regulation and the effects this may have on Notch activation under hypoxia.…”

Section: Introductionmentioning

confidence: 99%

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

Pietras

Stedingk

Lindgren

et al. 2011

Molecular Cancer Research

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Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on intracellular domain of the Notch1 receptor (icN1) stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1a dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, coculture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells. Mol Cancer Res; 9(5); 626-36. Ó2011 AACR.

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Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells

Cited by 30 publications

References 57 publications

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

A Combined Gene Signature of Hypoxia and Notch Pathway in Human Glioblastoma and Its Prognostic Relevance

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

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