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Arresting cancer

Researchers hope new discovery leads to drugs that halt cancer spread

Mayo Clinic researcher Dr. Panos Anastasiadis says the discovery is exciting because it may lead to the development of drugs that can halt the spread of cancerous tumors.

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Mayo Clinic researchers have found that a protein known to be a key component of the glue that holds cells together also is involved in breaking them apart and promoting their movement when tumors begin to spread to other parts of the body. The discovery illuminates the very first steps involved in the spread of cancer that makes the disease difficult to treat and suggests that a future drug might be able to block the beginning of this dangerous process — or stop it once it starts.

"This one protein, p120 catenin, is a key player in both suppressing invasion and promoting it," says the study's senior author, Panos Anastasiadis, Ph.D., a Mayo Clinic cancer researcher. "This is very exciting, because the findings open up a whole new field of discovery for novel therapeutics that should be applicable to most types of tumors."

Their laboratory study looks at how the protein interacts with different cadherin cell-adhesion proteins in cancer cells. Cadherin proteins go through a cell membrane, and on the outside, they act like Velcro, sticking to other cadherin proteins on adjacent cells.On the inside of the cell membrane, they bind, chain-like, to catenins, and catenins, in turn, regulate a cell's shape and function.

The best understood cadherin is E-cadherin, which provides tight connections between epithelial cells, forming a strong barrier like layer covering the inside of organs and body cavities and the outside skin of humans. "E-cadherin holds a human's cells and tissues together," Anastasiadis says.

Sometimes, such as during human development or wound repair, epithelial cells need to travel to other areas, and to do this, they undergo a process known as "epithelial-mesenchymal transition" (EMT). The cell reduces its production of E-cadherin proteins and increases expression of mesenchymal cadherins, loosening the anchors that keep the cell bound to its neighbors. Cancer, unfortunately, has adopted this strategy to spread, Anastasiadis says.

"When the function of E-cadherin is lost in a cell, it can break free from its neighbors and travel to settle elsewhere," he says. "This means that E-cadherin normally helps suppress invasion."

But researchers have noted that the p120 catenin protein seems mysteriously two-faced: while it normally strengthens cell-cell bonding, in some cases it can also negatively affect cell adhesion. They also have found that over-production of p120 increases a cell's ability to move. But the significance of these observations had eluded scientists.

In this study, Anastasiadis and co-author MasahiroYanagisawa, M.D., Ph.D., provide an answer for why p120 acts this way, which helps explain how cancer cells break away from tissue and spread.

"We show that E-cadherin suppresses invasion, at least in part, by binding to p120 protein in the cell," Anastasiadis says. "If E-cadherin is missing, p120 is free to bind to mesenchymal cadherins, setting off a process that leads to metastasis."

The investigators say that further research is needed but if the results continue to hold up, i tmight be therapeutically possible to selectively shut down the pro-invasive function of p120 while keeping pro-adhesion functional.

"We have provided a better understanding of the processes involved in the initiation of tumor spread,and it is this process that we all seek to shut down," Anastasiadis says.