title: Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.
abstract: Wilms' tumor (WT), the most frequent renal solid tumor in children, has been linked to aberrant Wnt signaling. Herein, we demonstrate that different WTs can be grouped according to either sensitivity or resistance to an antibody (Ab) specific to frizzled7 (FZD7), a Wnt receptor. In the FZD7-sensitive WT phenotype, the Ab induced cell death of the FZD7(+) fraction, which in turn depleted primary WT cultures of their clonogenic and sphere-forming cells and decreased in vivo proliferation and survival on xenografting to the chick chorio-allantoic-membrane. In contrast, FZD7-resistant WT in which no cell death was induced showed a different intra-cellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of β-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of β-catenin or WTX mutations. The addition of exogenous DKK1 and sFRP1 to the tumor cells enabled the sensitization of FZD7-resistant WT to the FZD7 Ab. Finally, although extremely difficult to achieve because of dynamic cellular localization of FZD7, sorting of FZD7(+) cells from resistant WT, showed them to be highly clonogenic/proliferative, overexpressing WT 'stemness' genes, emphasizing the importance of targeting this fraction. FZD7 Ab therapy alone or in combination with Wnt pathway antagonists may have a significant role in the treatment of WT via targeting of a tumor progenitor population.
authors.affiliation: Pediatric Stem Cell Research Institute, Safra Children's Hospital and Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Pode-Shakked
authors.forename: O
authors.initials: O
authors.lastname: Harari-Steinberg
authors.forename: Y
authors.initials: Y
authors.lastname: Haberman-Ziv
authors.forename: E
authors.initials: E
authors.lastname: Rom-Gross
authors.forename: S
authors.initials: S
authors.lastname: Bahar
authors.forename: D
authors.initials: D
authors.lastname: Omer
authors.forename: S
authors.initials: S
authors.lastname: Metsuyanim
authors.forename: E
authors.initials: E
authors.lastname: Buzhor
authors.forename: J
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: R S
authors.initials: RS
authors.lastname: Goldstein
authors.forename: M
authors.initials: M
authors.lastname: Mark-Danieli
authors.forename: B
authors.initials: B
authors.lastname: Dekel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000494:pharmacology; D005434:Flow Cytometry; D051157:Frizzled Receptors / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics; D009396:Wilms Tumor / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C501126:DKK1 protein, human; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases