Embryo’s cellular ‘dance’ may choreograph cancer, too
One of the classic examples of aberrant activation of a developmental pathway in cancer is the APC gene, a component of the Wnt signaling pathway. People with mutations in this gene, named for adenomatous polyposis coli, a pre-cancerous polyp found in the colon, have a high risk of developing colorectal cancer at a young age.
Prostaglandins appear to be involved. Researchers at Vanderbilt University Medical Center and elsewhere have found that drugs like aspirin, which interfere with prostaglandin signaling, can reduce colorectal cancer risk by up to 50 percent. “We’ve been on a quest for the last 10 years to understand why such a simple drug leads to such a significant reduction in cancer risk,” says Raymond DuBois, M.D., Ph.D., former director of the Vanderbilt-Ingram Cancer Center.
Developmental biology may help solve the mystery.
Prostaglandins are hormone-like substances involved in a wide range of physiological functions, including pain, inflammation and, in the case of a particular prostaglandin, PGE2, colorectal cancer.
In 2006, Vanderbilt researchers led by DuBois and Lilianna Solnica-Krezel, Ph.D., professor of Biological Sciences, identified a new role for prostaglandins in early embryogenesis. They found that prostaglandins help choreograph the intricate cell movements during the gastrulation phase of early embryonic development in zebrafish.
Treating zebrafish embryos with an inhibitor of PGE2 synthesis slowed down the cell movements of gastrulation. Blocking one of the prostaglandin receptors, EP4, caused similar abnormalities. The shapes and trajectories of embryonic cells were normal; they simply moved much more slowly. This suggested that prostaglandin signaling through the EP4 receptor regulates the speed of cell movements during gastrulation.
The results highlight how perturbations in this pathway might influence the spread of cancer as well as development. “The movements that happen in cancer might be, to some extent, recapitulation or modification of the normal migratory program that happens during normal development,” Solnica-Krezel says.
In 2005, researchers at the National Institutes of Health reported a direct link between the Wnt pathway and prostaglandin signaling. PGE2 increased the transport of Wnt-associated transcription factors into the nucleus of cultured colorectal tumor cells and enhanced proliferation.
“Understanding the role of the newly defined PGE2-regulated transcription factors and gene products may reveal additional therapeutic targets,” DuBois, currently provost and executive vice president of the University of Texas M.D. Anderson Cancer Center, wrote in a commentary on the NIH study.
Together, these two studies show that prostaglandins could regulate two cell activities, cell proliferation and movement, involved in tumor formation and metastasis, respectively. Their results could help explain how prostaglandins influence the development of colorectal cancer, and provide clues about the chemopreventive effects of non-steroidal anti-inflammatory drugs like aspirin.
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