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From left, Christo Venkov, David Plieth, Carol Xu, Dr. Eric Neilson, and Tsutomo Inoue. (photo by Dana Johnson)

Migratory ability of cancer cells examined

BY: CYNTHIA MANLEY

6/20/2003 - With few exceptions, people who die of cancer die not because of their primary tumor but because of cancer cells that spread to other vital parts of the body — the lungs, the brain, the liver.

Researchers at Vanderbilt and across the country are working to understand the process of metastasis, how cancer cells develop the ability to migrate from their original location, settle and begin growing in another distant organ. Much of this work is focused on the interactions between cancer cells and their neighboring cells (the tumor’s micro-environment) and how these interactions give cancer cells their ability to make this life-threatening invasion.

A group of Vanderbilt researchers, writing in the June 15 issue of the journal Cancer Research, describe in vivo proof of one potential mechanism used by cancer cells to become metastatic, epithelial-mesenchymal transition (EMT). They also identify a potential marker for cells on the brink of metastasis, a protein known as fibroblast-specific protein-1 (FSP1). This protein is selectively expressed by cells making this switch.

EMT is a process that epithelial cells, which are stationary, ordinarily use to transform into fibroblasts, a mobile type of cell involved in tissue repair and wound healing. The Vanderbilt team, using animal models, investigated the idea that breast epithelial cells use EMT for another purpose, to become more like fibroblasts so that they can move.

“This is an idea that is being discussed in the literature for a while and demonstrated in culture,” said Dr. Eric G. Neilson, Hugh J. Morgan Professor and Chair of Medicine, principal investigator in the study. “Our study is really the first major proof of this concept in vivo.”

Neilson’s co-authors are Chengsen Xue, David Plieth, Christon Venkov and Carol Xu of the departments of Medicine and Cell & Developmental Biology, as well as the Vanderbilt-Ingram Cancer Center.

The researchers found that fewer breast cancer tumors spread to the lungs in gene knockout mice that do not express FSP1 at all. They also reduced lung cancer metastases in mice that were genetically engineered to enable isolation of metastatic cells and insertion of a “suicide gene” to kill these cells.

“We found that if you interfere with EMT by killing the cells that are expressing this protein, or by eliminating the protein altogether, you significantly reduce metastases,” Neilson said.

The researchers were also able to tag the FSP1 gene with a fluorescent marker so that its expression could be observed. This finding suggests that FSP1 could be used to identify cells on the brink of becoming metastatic; if so, and if an approach could be developed to selectively kill these cells, it would provide a new way to control a cancer so that it is no longer life threatening.

With this knowledge, the researchers will further evaluate the role of EMT and FSP1 in tumor progression with an eye toward greater understanding of the process and its control.

The National Institutes of Health funded the work.

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