Elevated WNT2 Expression Detected in Circulating Pancreatic Cancer Cells

These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. Alternatively spliced transcript variants have been identified for this gene. The WNT pathway involves a large number of proteins that can regulate the production of WNT signaling molecules, their interactions with receptors on target cells and the physiological responses of target cells that result from the exposure of cells to the extracellular WNT ligands. Although the presence and strength of any given effect depends on the WNT ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms.

Investigators at Harvard Medical School (Boston, MA; USA) developed a novel microfluidic device for efficient capture of circulating tumor cells (CTCs) from both human patients and from mice with genetically induced pancreatic cancer.

They analyzed and compared RNA expression levels in pancreatic CTCs, in primary tumor cells, and in normal pancreatic tissue. Results published in the July 1, 2012, online edition of the journal Nature revealed that WNT2 expression was significantly elevated in both CTCs and metastatic cells while WNT2-expressing cells were rare in primary tumors. Nonetheless, WNT2 expression in pancreatic tumors was higher than in normal pancreatic tissue.

Drugs known to block the activity of various members of the WNT pathway were tested to determine whether they had any effect on pancreatic tumor metastasis. Chemical inhibition of the enzyme TGF-beta activated kinase 1 (TAK1) prevented metastasis-associated activities in cultured CTCs. Blocking TAK1 expression by siRNA interference also reduced the development of metastasis in mice injected with WNT2-expressing CTCs.

“This proof of principle study is the first to show that, by studying both mouse and human pancreatic cancer cells captured with this device, we can dissect genes that are overexpressed in these cells and identify signaling pathways that allow them to survive in the bloodstream,” said senior author Dr. Daniel Haber, professor of oncology at Harvard Medical School. “We also found that targeting a key step in these pathways can reduce metastatic potential, which is critically important for control of pancreatic cancer. This study would not have been possible without a way to isolate rare CTCs from both mouse models and human patients.”

“The picture in more complicated in humans, since multiple WNTs are upregulated,” said Dr. Haber. “But the TAK1 inhibitor we tested appears to have an effect on diverse WNT pathways involved in the survival of pancreatic CTCs. We previously reported that TAK1 inhibition has promise for treating a genetically defined subset of colon cancers, and these findings now extend the relevance of the TAK1 pathway to suppression of blood-borne metastasis in pancreatic cancer. Considerable more work will be needed to fully understand the critical pathways involved, but it is our hope that TAK1 inhibitors will ultimately be developed for clinical testing.”

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