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Scientists link gene to tumor metastasis
Charles W. Schmidt

For cancer patients and their doctors, few things are more worrisome than the threat of tumors spreading to other sites in the body. This process, known as metastasis, is responsible for more than 90 percent of all cancer deaths. Scientists at the Massachusetts Institute of Technology (MIT) and the Whitehead Institute in Cambridge, Massachusetts have identified a gene that plays an essential role in turning local tumors into metastatic killers. This finding, published in a recent issue of Nature, paves the way for diagnostic tests useful in predicting whether a cancer is likely to metastasize. "A diagnostic hit using the gene as a biomarker could have substantial implications for how a cancer patient is treated," suggests Edwin A. Clark, currently a researcher at Millennium Predictive Medicine in Cambridge, Massachusetts.

Clark's interest in the genetics of metastasis dates back to his early days as a post-doctoral fellow at the MIT Center for Cancer Research, where much of the current work was performed. Three years ago, he got a big leg up on his efforts when microarray technology came on the scene. "It's traditionally taken decades just to identify a few genes for a particular process," he explains. "But microarrays allow you to screen several thousand genes in a single pass. This is something we wanted to take advantage of in our own work."

That one gene could play such a critical role in metastasis came as an unexpected surprise

Together with researchers from the Whitehead Institute, Clark devised a model for using microarrays to identify genes whose expression correlates with metastasis. The goal was to compare the RNA profile of metastatic and non-metastatic cells derived from the same primary tumor. Clark used an in vivo model to select for cells with high metastatic potential. He began by taking poorly metastatic cell lines derived from human and mouse melanomas and injecting them intravenously into host mice. Cultured cells obtained from the few lung tumors that emerged had a high metastatic potential that increased with each successive generation of isolated cells. Clark used oligonucleotide microarrays to compare the expression of close to 10,000 genes obtained from tumor cells that metastasized to the lungs with those from non-metastatic subcutaneous tumors grown from the same parental cell lines. In all, 32 genes from the metastatic cells of either mouse or human were expressed at higher rates. And of these, three (fibronectin, thymosin b4, and RhoC) showed increased expression among metastases from both species.

The next step was to evaluate the influence of each of the three genes. Clark hit pay-dirt with his first selection, RhoC, which was chosen mainly for practical reasons: "RhoC comes from a super-family of genes that's already been extensively studied," he explains. The Rho super-family comprises a group of small GTP-hydrolyzing proteins, several of which are known to regulate cell migration. Clark found that adding RhoC induced a fifty-fold increase in metastasis among otherwise non-metastatic cells, and that conversely, addition of a mutant form of RhoC could inhibit metastasis in metastatic cells by as much as 80 percent. "In genetics, we call this a 'gain of function loss of function' experiment," says Richard Hynes, director of the Center for Cancer Research at MIT.

That one gene could play such a critical role in metastasis came as an unexpected surprise, especially given that the process itself is so complex. Clark thinks one reason RhoC is so important is that it might push some cells that are already close to metastasizing over the edge. "Some cells could become genetically primed for metastasis during the process of tumor evolution," he says. "It may be that all it takes is a single gene to induce them."

Even so, Clark and his colleagues doubt that RhoC is the only gene responsible for the process. The greater likelihood, they say, is that several genes are involved. Other potential targets of interest include the fibronectin and thymosin b4 genes, both of which are thought to participate in cellular migration, and possibly the other members of the Rho family: RhoA and RhoB. While interest in these other genes remains high, Clark intends to focus his near-term studies on RhoC and its expression in a larger sampling of human metastatic and non-metastatic tumors.

The greatest benefit may eventually be realized in improved diagnostic techniques

"We'll do the screen again when the entire human genome is available on chips," says Hynes. "That will give us a list of up to 100,000 genes and we'll use DNA arrays to look at all of them at once. This way we'll be able to screen lots of tumors quickly."

Although he doesn't discount the possibility, Clark is skeptical that these findings will be useful in developing a new drug to fight cancer. This is because a drug that targets RhoC may also inadvertently target other genes that are essential for normal cell growth and mobility. The greatest benefit may eventually be realized in improved diagnostic techniques, in which tumor biopsies can be screened rapidly for the expression of genes that have been found to be highly correlated with metastasis.

As significant as Clark's recent finding is the manner by which it was made. This is the first time that a gene identified with unbiased microarray technology has been experimentally validated in the laboratory. Up until now, most researchers have simply used microarrays to identify the genes that are associated with a particular disease condition, without testing whether addition or inhibition of the genes has any effect on biological processes. Clark's approach likely points to new directions in genomic research, and illustrates how information obtained from the human genome project will likely be used in the future.

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Clark, E.A., Golup, T.R., Lander, E.S. & Hynes, R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532-535 (August 3, 2000).

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