Phosphoinositide 3-kinases and regulation of embryonic stem cell fate

Welham, Melanie J.; Storm, Michael P.; Kingham, Emmajayne; Bone, Heather

doi:10.1042/bst0350225

Cited by 29 publications

(23 citation statements)

References 36 publications

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“…These findings are consistent with previous reports showing increased Akt activity in trastuzumab-resistant cell lines (Tanner et al, 2004;Kucab et al, 2005) and suggest that the PI3-K/ Akt pathway is important in mediating the effects of HER2 signaling. It is also consistent with recent reports suggesting a role for Akt signaling in stem cell selfrenewal (Welham et al, 2007) and in mediating treatment resistance (Ma et al, 2007;Saal et al, 2007). Most recently, Berns et al (2007) identified the PI3K pathway as a major determinant of trastuzumab resistance in human breast tumors using a functional genomic approach.…”

Section: Discussionsupporting

confidence: 89%

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

et al. 2008

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The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20-30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demonstrated by in vitro mammosphere assays and the expression of stem cell marker aldehyde dehydrogenase (ALDH) as well as by generation of hyperplastic lesions in humanized fat pads of NOD (nucleotide-binding oligomerization domain)/SCID (severe combined immunodeficient) mice. Overexpression of HER2 in a series of breast carcinoma cell lines increases the ALDH-expressing 'cancer stem cell' population which displays increased expression of stem cell regulatory genes, increased invasion in vitro and increased tumorigenesis in NOD/ SCID mice. The effects of HER2 overexpression on breast cancer stem cells are blocked by trastuzumab in sensitive, but not resistant, cell lines, an effect mediated by the PI3-kinase/Akt pathway. These studies provide support for the cancer stem cell hypothesis by suggesting that the effects of HER2 amplification on carcinogenesis, tumorigenesis and invasion may be due to its effects on normal and malignant mammary stem/progenitor cells. Furthermore, the clinical efficacy of trastuzumab may relate to its ability to target the cancer stem cell population in HER2-amplified tumors.

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Section: Discussionsupporting

confidence: 89%

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

et al. 2008

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“…3). The PI3K /AKT signaling cascade is known to be responsive to LIF and has been previously shown to trigger the expression of Nanog and to facilitate efficient proliferation and survival of murine ESC [24]. Based on these observations, we hypothesize that LIF is involved in maintenance of self renewal in porcine cells.…”

Section: Discussionmentioning

confidence: 80%

Culture Conditions and Signalling Networks Promoting the Establishment of Cell Lines from Parthenogenetic and Biparental Pig Embryos

Brevini

Pennarossa

Attanasio

et al. 2010

Stem Cell Rev and Rep

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The generation of porcine embryonic stem cells (pESC) would potentially have great impact in the biomedical field given the long-standing history of the pig as a prime animal model for pre-clinical biomedical applications. These cells would also be beneficial for the agricultural area, allowing efficient genetic engineering of this animal, to improve health and production traits. Despite numerous reports, no conclusive results have been obtained on the isolation and propagation of pESC lines and the establishment of pluripotent cells from the pig has remained an elusive goal. In the present study we performed a systematic analysis of different culture media for their ability to support the establishment of homogenous outgrowths from in vitro-produced embryos. Furthermore, we investigated which molecular networks are responsive to the factors contained in the most efficient media, since the identification of dominant signaling pathways that regulate porcine stem-cell pluripotency is likely to facilitate the generation of genuine pESC. Finally we compared IVF blastocysts versus parthenotes as a possible source for putative pESC in terms of blastocyst rate, resilience to immunosurgery procedures, ability to attach to the feeder, to generate outgrowths and to establish stable cell lines.

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“…Due to its essential role in cell survival, the PI3K/Akt pathway and inositol phosphatases that regulate it are proposed to play a role in stem cell self-renewal, maintenance, and differentiation. This includes several types of stem cells, including pluripotent stem cells, [31,[62][63][64][65] HSC, [20,22,[66][67][68] neural stem cells [69][70][71][72][73][74], and epithelial stem cells [75]. A recurring theme in several stem cell types is for the PI3K/Akt pathway to inactivate GSK3b thus promoting activation and nuclear translocation of b-catenin [76,77].…”

Section: Discussionmentioning

confidence: 99%

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Iyer

Viernes

Chisholm³

et al. 2014

Stem Cells and Development

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Here, we show that Src homology 2-domain-containing inositol 5¢-phosphatase 1 (SHIP1) is required for the efficient development of osteoblasts from mesenchymal stem cells (MSCs) such that bone growth and density are reduced in mice that lack SHIP1 expression in MSCs. We find that SHIP1 promotes the osteogenic output of MSCs by limiting activation of the PI3K/Akt/b-catenin pathway required for induction of the MSC stemness factor Id2. In parallel, we demonstrate that mice with myeloid-restricted ablation of SHIP1, including osteoclasts (OCs), show no reduction in bone mass or density. Hence, diminished bone mass and density in the SHIP1-deficient mice results from SHIP deficiency in MSC and osteolineage progenitors. Intriguingly, mice with a SHIP-deficient MSC compartment also exhibit decreased OC numbers. In agreement with our genetic findings we also show that treatment of mice with an SHIP1 inhibitor (SHIPi) significantly reduces bone mass. These findings demonstrate a novel role for SHIP1 in MSC fate determination and bone growth. Further, SHIPi may represent a novel therapeutic approach to limit bone development in osteopetrotic and sclerotic bone diseases.

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Phosphoinositide 3-kinases and regulation of embryonic stem cell fate

Cited by 29 publications

References 36 publications

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

Culture Conditions and Signalling Networks Promoting the Establishment of Cell Lines from Parthenogenetic and Biparental Pig Embryos

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

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