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Oct 28, 2010

Tumor Suppressor Found to Act as Oncogene in Glioblastoma

  • Epithelial cadherin (E-cadherin), which is thought to be a tumor suppressor, appears to act as an oncogene in glioblastoma, according to researchers at Mayo Clinic in Florida. They say the findings, published online in PLoS ONE, could explain recent, puzzling observations about E-cadherin expression in breast cancer, for example.

    While loss of E-cadherin is generally considered a harbinger of metastasis, researchers have also found that most breast cancer that has spread retains E-cadherin expression. Ovarian tumors also have been found to produce more E-cadherin as they grow.

    “This surprising finding should compel us all to shift our thinking about E-cadherin,” remarks the study's lead investigator, Panos Z. Anastasiadis, Ph.D. “Up to now, we have all thought that if a tumor loses E-cadherin function, that represents a movement toward metastasis. That makes sense because 50 percent of cancers don't express E-cadherin, and they are linked to a worse prognosis. But now it appears that E-cadherin expression in a tumor could be responsible for cells growing out of control if the protein is not functioning as it should be.”

    Dr. Anastasiadis’ research team examined protein expression in glioblastoma cancer cells. “Our interest is to understand the pathways that induce glioblastoma to be so invasive. The problem with this cancer is that the tumors can be very aggressive, and single cancer cells can spread all over the brain.”

    Among other proteins, the researchers looked at cadherins, of which about 20 are expressed in the brain, more than in any other organ. These are transmembrane proteins that play critical roles in determining how cells bind to each other in a tissue. The researchers expected to find significant amounts of neural cadherin (N-cadherin) in the tumors but not E-cadherin, which is expressed in epithelial rather than normal brain tissue.

    In epithelial tissue, loss of E-cadherin usually represents a switch in cell behavior known as epithelial-mesenchymal transition (EMT). In EMT, cells that had been tightly bound to each other loosen up, due to loss of E-cadherin and other proteins including other members of the cadherin superfamily. This promotes migration of individual cells away from a cancer cluster.

    While N-cadherin was expressed in most human brain tumor cell lines—and N-cadherin is potentially oncogenic—some also expressed E-cadherin. Additionally, they found those cells that expressed E-cadherin acted more aggressively than brain cancer that did not express the protein.

    The researchers say they then validated their findings in animal studies. Finally, they performed an experiment in which they removed E-cadherin expression from glioblastoma cells. The team found these cells had a reduced ability to move and grew at a much slower pace.

    “E-cadherin expressed in these glioblastomas did not function to keep cells stuck together,” Dr. Anastasiadis says. “Instead, they promoted tumor growth and migration. This is the complete opposite of what we have known about E-cadherin. For some reason, in these brain cells, E-cadherin expression is linked to aggressive cell behavior and poor prognosis.

    “Understanding what causes the switch in E-cadherin function from a tumor suppressor to an oncogene and how to block it will be critical,” concludes Dr. Anastasiadis. “But the bottom line is that we cannot view E-cadherin simply as a tumor suppressor anymore.”


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