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

Bielen A, Box G, Perryman L, Bjerke L, Popov S, Jamin Y, Jury A, Valenti M, Brandon Ade H, Martins V, Romanet V, Jeay S, Raynaud FI, Hofmann F, Robinson SP, Eccles SA, Jones C.
Journal   Proc Natl Acad Sci U S A.
Species  
Analytes Measured   Akt , IGF-1R , IRS-1
Matrix Tested   Cell lysates, tumor xenograft lysates, nephroblastoma, MAPK, PI3-kinase
Year   2012
Volume   109
Page Numbers   1267-1276
Application   Phosphoproteins
Abstract
We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G(1) cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the kidney were histologically accurate and exhibited significantly elevated insulin-like growth factor-mediated signaling, and growth was significantly reduced on treatment with NVP-AEW541 in parallel with signaling pathway ablation. As a result of the paracrine effects of enhanced IGF2 expression in Wilms tumor, this disease may be acutely dependent on signaling through the IGF1 receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such efficacy may be missed if only standard ectopic models are considered as a result of an imperfect recapitulation of the specific tumor microenvironment.

View Publications

Related Products

Insulin Signaling Panel (Phospho Protein) Kit
IGF-1R, IR, IRS-1 | Human
Multiplex
Phospho/Total ERK1/2 Whole Cell Lysate Kit
ERK-1/2 (total) | Human, Mouse, Rat
Multiplex
Phospho(Ser473)/Total Akt Whole Cell Lysate Kit
Akt | Human, Mouse, Rat
Multiplex
R-PLEX Human IRS-1 Assay
IRS-1 | Human
Singleplex
R-PLEX Human IRS-1 Antibody Set
IRS-1 | Human
Akt Control Pack 1
Akt
Total Akt Kit
Akt | Human, Mouse, Rat, Non-human primate
Singleplex
Phospho-Akt (Ser473) Kit
Akt | Human, Mouse, Rat, Non-human primate
Singleplex
Akt Signaling Panel II Whole Cell Lysate Kit
Akt, GSK-3β, p70S6K, S6RP | Human, Mouse, Rat
Multiplex
Akt Signaling (Total Protein) Whole Cell Lysate Kit
Akt, GSK-3β, p70S6K | Human, Mouse, Rat
Multiplex
Akt Signaling Whole Cell Lysate Kit
Akt, GSK-3β, p70S6K | Human, Mouse, Rat
Multiplex
Phospho-Akt (Thr308) Whole Cell Lysate Kit
Akt | Human, Mouse
Singleplex
Phospho-Akt (Ser473) Antibody
Akt
Total Akt Antibody Bulk Product
Akt
Browse Our Products

By Analytes
By Applications
Search
Customer Service/Orders


Scientific/Technical Support


Instrument Support


Company Headquarters