Hyperactive Wnt Signaling Drives Sarcoma Formation

Overexpression of the Wnt signaling pathway is a driving force behind the development and expansion of human sarcomas.

Sarcomas comprise about 1% of all adult cancers, but about 15% of all childhood cancers. About 20% of sarcomas are curable by surgery, while 30% can be cured by surgery with chemotherapy and/or radiation.

Normal Wnt functioning is critical for maintaining tissue homeostasis. Hyperactive Wnt signaling has been reported to be one of the early causes of colon cancer, and it has also been implicated in several other cancer types. In the current study, investigators at the Mount Sinai School of Medicine (New York, NY, USA) examined the relationship between Wnt signaling and sarcoma development.

Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer.

Results published in the May 17, 2011, issue of the journal Cancer Cell revealed that 50% of human sarcomas and 65% of sarcoma cell lines of diverse histological subtypes exhibited upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, there were alterations including overexpression or gene amplification of Wnt ligands. Hyperactive Wnt signaling increased the growth of several subtypes of human sarcoma cells by increasing the expression of CDC25A, a gene previously shown to be deregulated in various types of cancer. Suppression of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the down-regulation of CDC25A.

Several cancer types show increased CDC25A levels, and it is regarded as a good target to generate therapeutic agents to dampen its activity. "The prevalence of Wnt signaling hyperactivity in human sarcoma cells gives researchers a potential new target as they develop medications to target human sarcoma," said senior author Dr. Stuart Aaronson, professor of oncological sciences at Mount Sinai School of Medicine.

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