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 þ 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 intracellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of b-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of b-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 þ 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.

The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells

“…These data suggest that FZD7-Fab leads to FZD7 degradation, potentially through internalization, so that the receptor is no longer available for Wnt3a binding and signaling. FZD7 receptor internalization has also been observed in Wilms' tumor cells treated with anti-FZD7 antibody (23).…”

Secreted Frizzled Related Protein 1 Modulates Taxane Resistance of Human Lung Adenocarcinoma

“…Accumulating evidence shows that SFRP1 exerts inhibitory effects on tumor cell growth, angiogenesis and invasion (31)(32)(33). SFRP1 was decreased significantly in frizzled7 (FZD7)-resistant Wilms tumor, and exogenous administration of SFRP1 could sensitize resistant cells to FZD7 antibody (34). Combinatorial treatment of renal cell carcinoma cell lines with decitabine and romidepsin induced the reexpression of SFRP1 (35).…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…However, their inherent traits, which allow them to escape conventional Targeting the human WT NCAM1 + cell fraction with an anti-NCAM1 antibody-toxin conjugate (HuN901-DMI) resulted in loss of the WT CSCs, followed by complete tumor degradation chemo/radiotherapies, necessitate the development of alternative treatment options directed at these highly malignant and therapy-resistant cancer cells. Although therapeutics aimed at CSC eradication have not yet reached clinical use, there are several novel reports of targeted CSC therapy in animal models or in clinical trials [62,63].…”