Notch and Epithelial-Mesenchyme Transition in Development and Tumor Progression: Another Turn of the Screw

Grego-Bessa, Joaquím; Díez, Juan; Timmerman, Luika; Jl, de la Pompa

doi:10.4161/cc.3.6.949

Cited by 107 publications

(87 citation statements)

References 40 publications

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“…Interestingly, TGF␤/BMPs and other pathways like wingless/Wnt, Notch, and Hedgehog seem not only to be involved in bone development/homeostasis and hematopoiesis but also in prostate cancer initiation and progression. 2,8,[53][54][55][56] Our in vitro and in vivo data further support the notion that BMP7 can antagonize TGF␤ signaling routes in human prostate cancer cells that are metastatic to the skeleton.…”

Section: Bmp7 and Prostatesupporting

confidence: 65%

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Buijs

Rentsch

Horst

et al. 2007

The American Journal of Pathology

180

160

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Bone morphogenic protein 7 (BMP7) counteracts physiological epithelial-to-mesenchymal transition, a process that is indicative of epithelial plasticity. Because epithelial-to-mesenchymal transition is involved in cancer, we investigated whether BMP7 plays a role in prostate cancer growth and metastasis. BMP7 expression in laser-microdissected primary human prostate cancer tissue was strongly down-regulated compared with normal prostate luminal epithelium. Furthermore, BMP7 expression in prostate cancer cell lines was inversely related to tumorigenic and metastatic potential in vivo and significantly correlated to E-cadherin/vimentin ratios. Exogenous addition of BMP7 to human prostate cancer cells dose-dependently inhibited transforming growth factor ␤-induced activation of nuclear Smad3/4 complexes via ALK5 and induced E-cadherin expression. Moreover, BMP7-induced activation of nuclear Smad1/4/5 signaling transduced via BMP type I receptors was synergistically stimulated in the presence of transforming growth factor ␤, a growth factor that is enriched in the bone microenvironment. Daily BMP7 administration to nude mice inhibited the growth of cancer cells in bone. In contrast, no significant growth inhibitory effect of BMP7 was observed in intraprostatic xenografts. Collectively, our observations suggest that BMP7 controls and preserves the epithelial phenotype

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Section: Bmp7 and Prostatesupporting

confidence: 65%

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Buijs

Rentsch

Horst

et al. 2007

The American Journal of Pathology

180

160

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“…Two upstream EMT inducers regulate EMT during development and tumor progression: the TGF-b and Notch families. 3,13 Both families contribute to tumor …”

mentioning

confidence: 99%

“…Two upstream EMT inducers regulate EMT during development and tumor progression: the TGF-b and Notch families. 3,13 Both families contribute to tumor development, where they can act independently or cooperatively in the regulation of EMT progression. 13 The Notch signaling pathway is known to have a primary role in cell fate determination during organ development, and Notch controls liver development by regulating biliary 14 and hepatoblast 15 differentiation.…”

mentioning

confidence: 99%

“…3,13 Both families contribute to tumor development, where they can act independently or cooperatively in the regulation of EMT progression. 13 The Notch signaling pathway is known to have a primary role in cell fate determination during organ development, and Notch controls liver development by regulating biliary 14 and hepatoblast 15 differentiation. However, aberrant activation of the Notch pathway has also been shown to be involved in tumorigenesis and the development of EMT in several cancer types.…”

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confidence: 99%

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Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the reestablishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and is ranked second amongst all cancer deaths in Hong Kong. HCC is correlated with an increased likelihood of vascular invasion, metastasis and recurrence (even after surgical resection), leading to poor prognosis. 1 Metastasis, both intrahepatic and extrahepatic, is of particular concern and occurs in more than half of HCC cases. 2 The incidence of high grade HCC that metastasize to distant sites is high. 2 However, the detailed mechanisms of metastasis are yet to be revealed.The process that converts adherent epithelial cells into migratory cells to invade the extracellular matrix is called the epithelial-mesenchymal transition (EMT). This process plays fundamental roles in tissue and organ formation during embryonic development and in wound healing and tissue repair during adult life. 3,4 However, the abnormal activation of EMT programs can be disadvantageous to cancer patients. 3 EMT can allow carcinoma cells to acquire mesenchymal cell gene expression profiles and properties, 5 leading to the transformation of the cells from being coherent and displaying apicobasal polarity to become nonpolarized cells that can move through the extracellular media. This transformation enables the spread of tumor cells to distant sites. 6,7 Although EMT is considered to be the first step in the metastatic progression of migratory cancer cells, EMT has not been confirmed to exist in vivo. 3...

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“…N otch signaling functions in a variety of developmental contexts in different embryonic and tissue systems (1). The main framework of the pathway is evolutionarily conserved; thus, its many roles reflect cooption of an ancestral signaling pathway.…”

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confidence: 99%

MAPK regulation of maternal and zygotic Notch transcript stability in early development

Gonsalves

Weisblat

2007

Proc. Natl. Acad. Sci. U.S.A.

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Spatiotemporal modulation of the evolutionarily conserved, intercellular Notch signaling pathway is important in the development of many animals. Examples include the regulation of neuralepidermal fate decisions in neurogenic ectoderm of Drosophila and somitogenesis in vertebrate presomitic mesoderm. In both these and most other cases, it appears that Notch-class transmembrane receptors are ubiquitously expressed. Modulation of the pathway is achieved primarily by the localized expression of the activating ligand or by alteration of receptor specificity through a glycosyl transferase. In contrast, we present this report of an instance where the abundance of the Notch-class mRNA itself is dynamically regulated. Taking advantage of the long cell cycle of the two-cellstage embryo of the leech Helobdella robusta, we show that this regulation is achieved at the levels of both transcript stability and transcription. Moreover, MAPK signaling plays a significant role in regulating accumulation of the transcript by virtue of its effect on Hro-notch mRNA stability. Intracellular injection of heterologous reporter mRNAs shows that the Hro-notch 3 UTR, containing seven AU-rich elements, is key to regulating transcript stability. Thus, we show that regulation of the Notch pathway can occur at a previously underappreciated level, namely that of transcript stability. Given that AU-rich elements occur in the 3 UTR of Notch-class genes in Drosophila, human, and Caenorhabditis elegans, regulation of Notch signaling by modulation of mRNA levels may be operating in other animals as well.Helobdella ͉ leech ͉ mRNA turnover ͉ 3Ј UTR

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Notch and Epithelial-Mesenchyme Transition in Development and Tumor Progression: Another Turn of the Screw

Cited by 107 publications

References 40 publications

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in Vivo

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

MAPK regulation of maternal and zygotic Notch transcript stability in early development

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