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Connection found between hyperactive Wnt protein signaling pathway and sarcoma
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The discovery of hyperactive signals along the Wnt pathway in human sarcoma cells by researchers at Mount Sinai School of Medicine could lead to new targeted sarcoma treatments.
“The high frequency of Wnt pathway activation observed in human sarcoma cells makes this pathway an ideal candidate for future therapeutic interventions in the treatment of this disease,” Stuart A. Aaronson, MD, chairman of Oncological Sciences at Mount Sinai School of Medicine and lead investigator of the study, told HemOnc Today.
Wnt signaling is involved in the regulation, renewal and differentiation of mesenchymal stem cells. Sarcomas, which account for a large fraction of pediatric tumors, involve mesenchymal tissues and constitute many histological subtypes. Previous research by Aaronson and colleagues showed that human mesenchymal stem cells have low levels of endogenous Wnt signaling, which decreases according to differentiation stimuli, but that when exogenous Wnt was added to these cells, their differentiation was inhibited.
Building on these findings, Aaronson and his team sought to identify the possible connection between an overactive Wnt pathway and sarcomas. The researchers identified upregulated levels of uncomplexed beta-catenin and increased T-cell specific transcription factor reporter activity, two biochemical tools used to measure Wnt activity in cells, in 17 of 23 sarcoma lines of distinct subtypes. They then screened a variety of soft tissue and bone sarcomas for uncomplexed beta-catenin levels. Of 45 primary sarcomas analyzed, Wnt activation was found in 25, spanning 12 histological subtypes.
To identify differentially expressed genes, the investigators used a gene expression microarray and isolated CDC25A as a Wnt transcriptional target, as indicated by the beta-catenin dependent activation in sarcoma cells of the CDC25A reporter. The researchers also discovered that CDC25A was an important mediator of both in vitro and in vivo Wnt-induced sarcoma cell proliferation.
“There are several independent laboratories currently trying to develop therapeutic measures to target CDC25A, which is reported to be overexpressed in other cancer types as well,” said lead author, Sapna Vijayakumar, PhD, an instructor of Oncological Sciences at Mount Sinai School of Medicine.
Animal studies have shown that among the CDC25 family, CDC25A has a non-redundant role in regulating cell cycle; it is overexpressed in a number of cancers, including breast, ovarian, colorectal, and head and neck. Aaronson and colleagues concluded that, “Wnt upregulation by autocrine activation or other mechanisms plays an important causal role in the proliferative drive of Wnt-activated sarcomas through a Wnt target gene CDC25A.” – by Whitney McKnight
For more information:
- Vijayakumar S. Cancer Cell. 2011;19:601-612.
- Vijayakumar S. Cancer Cell. 2011;doi 10.1016/j.ccr.2011.03.010
Disclosure: Drs. Aaronson and Vijayakumar report no financial disclosures.