TY - JOUR
T1 - Resistance or sensitivity of Wilms tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target
AU - Pode-Shakked, N.
AU - Harari-Steinberg, O.
AU - Haberman-Ziv, Y.
AU - Rom-Gross, E.
AU - Bahar, S.
AU - Omer, D.
AU - Metsuyanim, S.
AU - Buzhor, E.
AU - Jacob-Hirsch, J.
AU - Goldstein, R. S.
AU - Mark-Danieli, M.
AU - Dekel, B.
N1 - Funding Information:
We thank Lior Zangi, Tsahi Neuman and Igor Grinberg for technical assistance. This work was supported by ISF grant number 1139/07, ICRF Clinical Career Development Award, TAU Cancer Biology Research Center and TAU Stem Cell Research Center, The Schreiber and Brettler Foundations, Sackler School of Medicine, Tel Aviv University (BD). This work is part of the requirements toward a PhD degree, Sackler School of Medicine, Tel Aviv University (NPS).
PY - 2011/4/7
Y1 - 2011/4/7
N2 - 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.
AB - 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.
KW - Wilms' tumor
KW - frizzled7
KW - resistant
KW - sensitive
KW - stem cells
KW - wnt pathway
UR - http://www.scopus.com/inward/record.url?scp=79953795334&partnerID=8YFLogxK
U2 - 10.1038/onc.2010.549
DO - 10.1038/onc.2010.549
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C2 - 21472018
AN - SCOPUS:79953795334
SN - 0950-9232
VL - 30
SP - 1664
EP - 1680
JO - Oncogene
JF - Oncogene
IS - 14
ER -