Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas

Cantilena, Sandra; Pastorino, Fabio; Pezzolo, Annalisa; Chayka, Olesya; Pistoia,; Ponzoni, Mirco; Sala, Arturo

doi:10.18632/oncotarget.410

Cited by 64 publications

(64 citation statements)

References 20 publications

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“…HIF-2α, but not HIF-1α, is induced under hypoxic conditions and upregulation of this factor is critical to maintaining the tumorigenicity of glioma stem cells [41]. Coexpression of the Wnt receptor-Frizzled receptor 6, with HIF1/2α in hypoxic areas of primary human neuroblastomas tumors is characteristic of a population of rare, highly tumorigenic stem-like cells [42]. Interaction of HIF-1α and Notch3, which is required for the expression of the hypoxia-responsive gene Carbonic Anhydrase 9, is a potential target for cancer/stem cell therapy [43].…”

Section: Discussionmentioning

confidence: 99%

Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB–HIF-1α pathway

et al. 2015

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There is increasing evidence to suggest that hepatocellular carcinomas (HCCs) are sustained by a distinct subpopulation of self-renewing cells known as cancer stem cells. However, the precise signals required for maintenance of stemness-like properties of these cells are yet to be elucidated. Here, we demonstrated that the level of oncoprotein osteopontin (OPN) in tumor cells of the edge of bulk tumors was significantly correlated with the clinical prognosis of patients with HCC. OPN was highly expressed in side population fractions of HCC cell lines, as well as in dormant cells, spheroids and chemo-resistant cancer cells, all of which are considered as having stemness-like cellular features. Depletion of OPN in HCC cell lines resulted in a reduction in the proportion of side population fractions, formation of hepato-spheroids, expression of stem-cell-associated genes and decreased tumorigenecity in immunodeficient mice. Mechanistically, OPN was demonstrated to bind to integrin αvβ3 and activate the transcription factor NF-κB, which resulted in upregulation of HIF-1α transcription and its downstream gene, BMI1, to mediate maintenance of the stemness-like phenotype. Suppression of the αvβ3–NF-κB–HIF-1α pathway decreased OPN-mediated self-renewal capabilities. Levels of OPN protein expression were significantly correlated with HIF-1α protein levels in HCC tumor tissue samples. OPN might promote a cancer stem cell-like phenotype via the αvβ3–NF-κB–HIF-1α pathway. Our findings offer strong support for OPN requirement in maintaining stem-like properties in HCC cells.

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Section: Discussionmentioning

confidence: 99%

Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB–HIF-1α pathway

et al. 2015

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“…Additionally, the expression of FZD6 is reported to predict poor survival in neuroblastoma patients, and marks rare and highly tumorigenic neuroblastoma stem cells (Cantilena et al, 2011). Furthermore, microarray analysis of Tet21N MYCN+ and MYCN− cells identified that in addition to DKK1 and DKK3 , there was deregulated expression of several components of the Wnt pathway in the presence of MYCN.…”

Section: Dkk3mentioning

confidence: 99%

p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance

Chen¹,

Tweddle²

2012

Front. Oncol.

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Neuroblastoma is the most common extra-cranial solid tumor of childhood. Despite significant advances, it currently still remains one of the most difficult childhood cancers to cure, with less than 40% of patients with high-risk disease being long-term survivors. MYCN is a proto-oncogene implicated to be directly involved in neuroblastoma development. Amplification of MYCN is associated with rapid tumor progression and poor prognosis. Novel therapeutic strategies which can improve the survival rates whilst reducing the toxicity in these patients are therefore required. Here we discuss genes regulated by MYCN in neuroblastoma, with particular reference to p53, SKP2, and DKK3 and strategies that may be employed to target them.

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“…Although many factors that affect the tumorigenesis and metastasis of NB have been identified in recent years, such as signal transducer and activator of transcription 3 [4], Frizzled receptor 6 [5], and focal adhesion kinase [6], better elucidation of the mechanisms for the aggressive progression of NB is needed for improving the therapeutic efficiencies. Neural crest development is a complex and multi-step process, involving a series of inductive signals and responding transcription factors [7].…”

Section: Introductionmentioning

confidence: 99%

FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma

Hong

et al. 2013

Oncotarget

100

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The transcription factor forkhead box D3 (FOXD3) plays a crucial role in the development of neural crest cells. However, the function and underlying mechanisms of FOXD3 in the progression of neuroblastoma (NB), an embryonal tumor that is derived from the neural crest, still remain largely unknown. Here, we report that FOXD3 is an important oncosuppressor of NB tumorigenicity and aggressiveness. We found that FOXD3 was down-regulated in NB tissues and cell lines. Patients with high FOXD3 expression have greater survival probability. Over-expression or knockdown of FOXD3 responsively altered both the protein and mRNA levels of N-myc downstream regulated 1 (NDRG1) and its downstream genes, vascular endothelial growth factor and matrix metalloproteinase 9, in cultured NB cell lines SH-SY5Y and SK-N-SH. Luciferase reporter and chromatin immunoprecipitation assays indicated that FOXD3 directly targeted the binding site within NDRG1 promoter to facilitate its transcription. Ectopic expression of FOXD3 suppressed the growth, invasion, metastasis and angiogenesis of SH-SY5Y and SK-N-SH cells in vitro and in vivo. Conversely, knockdown of FOXD3 promoted the growth, migration, invasion and angiogenesis of NB cells. In addition, rescue experiments in FOXD3 over-expressed or silenced NB cells showed that restoration of NDRG1 expression prevented the tumor cells from FOXD3-mediated changes in these biological features. Our results indicate that FOXD3 exhibits tumor suppressive activity that affects the growth, aggressiveness and angiogenesis of NB through transcriptional regulation of NDRG1.

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Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas

Cited by 64 publications

References 20 publications

Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB–HIF-1α pathway

Osteopontin promotes a cancer stem cell-like phenotype in hepatocellular carcinoma cells via an integrin-NF-κB–HIF-1α pathway

p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance

FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma

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