Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Bielen, Aleksandra; Box, Gary; Perryman, Lara; Bjerke, Lynn; Popov, Sergey; Jamin, Yann; Jury, Alexa; Valenti, Melanie; Brandon, Alexis de Haven; Martins, Vanessa; Romanet, Vincent; Jeay, Sébastien; Raynaud, Florence I.; Hofmann, Francesco; Robinson, Simon P.; Eccles, Suzanne A.; Jones, Chris

doi:10.1073/pnas.1105034109

Cited by 32 publications

(33 citation statements)

References 36 publications

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“…To elucidate the functionality of IRX3 and IRX5 in Wilms tumour development, targeted genome editing of IRX3 and IRX5 was performed on the human WiT49 Wilms tumour cell line, chosen as a model system as it retains the multi‐phasic histology of Wilms tumours when orthotopically xenografted into mice . Most importantly, the model enables the evaluation of tumour tubule formation, corresponding to Wilms tumour epithelial differentiation.…”

Section: Resultsmentioning

confidence: 99%

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Mengelbier

Lindell-Munther

Yasui

et al. 2018

The Journal of Pathology

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Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock‐out Irx3 − /Irx5 − mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 −/− cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β‐catenin‐signalling. In contrast, IRX5 −/− cells displayed activation of Hippo and non‐canonical WNT‐signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

Mengelbier

Lindell-Munther

Yasui

et al. 2018

The Journal of Pathology

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“…Similarly, its gene expression pattern was unique from Wilms tumor cell lines, and it carried none of the common genomic aberrations common seen in Wilms tumor 50 . Lastly, unlike true Wilms tumor cell lines, WT-CLS1 showed a unique resistance to IGF1R inhibition 51 . Our recharacterization here explains these previously confusing results.…”

Section: Discussionmentioning

confidence: 97%

miR-16 Suppresses Growth of Rhabdoid Tumor Cells

Stroup

Yeu

Budhipramono

et al. 2017

Preprint

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BackgroundRhabdoid tumor is a highly aggressive pediatric cancer characterized by biallelic loss and/or mutation of SMARCB1. Outcomes remain poor, and there are no established ways to target the tumorigenic pathways driven by SMARCB1 inactivation. SMARCB1 loss leads to an increase in cyclin D transcription.ProcedureWe characterized the cell line WT-CLS1, which has been described previously as Wilms tumor, by whole-exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WT-CLS1, BT-12, and CHLA-06-ATRT.ResultsWe found that WT-CLS1 demonstrates the histological, mutational, and transcriptional hallmarks of rhabdoid tumor. Because the microRNAs let-7 and miR-16 can target cyclin D genes, we next overexpressed each of these microRNAs in WT-CLS1. We found that miR-16 reduced cell accumulation. This was accompanied by a decrease in proliferation markers and an increase in apoptosis markers. These results were replicated in the BT-12 and CHLA-06-ATRT cell lines.ConclusionsThe loss-of-function SMARCB1 mutation found in WT-CLS1, in conjunction with immunohistochemical and gene expression analysis, warrants reclassification of this cell line as rhabdoid tumor. Proliferation of WT-CLS1 and other rhabdoid tumor cell lines is significantly abrogated by miR-16 overexpression. Further studies are necessary to gain insight into the potential for miR-16 to be used as a novel therapeutic in rhabdoid tumor.Abbreviations(ATRT)atypical teratoid/rhabdoid tumor(miRNA)microRNA(dox)doxycycline(OD595)optical density at 595 nm(CDK4)cyclin-dependent kinase 4

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“…IGF2 binds to the IGF1 receptor (IGFIR) and is over-expressed in Wilms tumour patients. In vitro studies showed that inhibition of IGFIR suppressed growth of Wilms tumour cells (31), suggesting that indeed growth factor excess may be an important determinant of clinical overgrowth in survivors of Wilms tumour. It is important to realize that IGF2 is a potent fetal growth factor and plays a significant role in particularly overgrowth syndromes but is not responsible for linear growth, like IGF1.…”

Section: Discussionmentioning

confidence: 99%

Final height and IGF1 in adult survivors of Wilms tumour

Blijdorp

Heuvel‐Eibrink

Pieters

et al. 2013

European Journal of Endocrinology

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Objective: One-sided nephrectomy is followed by increased levels of IGF1, associated with linear growth during childhood. The aim was to evaluate final height and IGF1 levels in nephrectomized Wilms tumour survivors when compared with healthy Dutch references and survivors of other cancer types. Design: Cross-sectional retrospective study. Methods: Data of 575 adult childhood cancer survivors were analysed. Median follow-up time was 17.8 (range 5.0-48.8) years. Analysis of (co)variance was performed to evaluate differences between subgroups: nephrectomized Wilms survivors treated with or without abdominal irradiation (nZ41 and nZ36) and survivors of other cancer types treated with or without irradiation involving the cranium, abdomen or total body (nZ149 and nZ349). Main outcome measures were IGF1 and height, expressed as SDS. Results: After adjustment for age at diagnosis, former corticosteroid treatment and renal impairment, height SDS in non-irradiated nephrectomized Wilms survivors was significantly higher than that in non-irradiated survivors of other cancer types (estimated mean SDS K0.09 vs K0.49, PZ0.044), abdominal irradiated survivors (SDS K0.70, PZ0.015) and other irradiated survivors (SDS K1.47, P!0.001). Non-irradiated nephrectomized Wilms tumour survivors had significantly higher IGF1 SDS than other irradiated survivors (estimated mean SDS K0.05 vs K1.36, P!0.001 and 0.11 vs 1.37, P!0.001), while there was no significant difference with the other two subgroups. Conclusions: Adult survivors of Wilms tumour showed better attainment of final height and relatively higher IGF1 levels than those of other cancer types who had significantly shorter stature and lower IGF1 levels than Dutch references.

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Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition

Cited by 32 publications

References 36 publications

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis

miR-16 Suppresses Growth of Rhabdoid Tumor Cells

Final height and IGF1 in adult survivors of Wilms tumour

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