August 10, 2001

Vanderbilt investigators chase “Pac-Man” proteins

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Howard Crawford, Ph.D., and Lynn M. Matrisian, Ph.D., are studying molecular defects that affect invasive cancer. (photo by Dana Johnson)

Vanderbilt investigators chase “Pac-Man” proteins

Howard Crawford, Ph.D., and colleagues are working backwards in order to move forward in the search for molecular defects that give rise to invasive cancer.

The Vanderbilt-Ingram Cancer Center investigators know that when cancer cells turn aggressive, they make proteins called matrix metalloproteinases (MMPs). These tiny Pac-Man-like proteins munch away at the glue that holds cells in place, freeing the cancer cells to invade and metastasize. So the researchers are starting at the end – with the MMP genes – and they’re “tracing backwards, looking for the signals that turn on the MMPs,” said Crawford, a research assistant professor of Cancer Biology working with Lynn M. Matrisian, Ph.D., Ingram Professor of Cancer Research and chair of Cancer Biology.

At a time when many researchers are using genomics approaches to identify genes that have altered expression in cancer cells, the strategy of starting with a known gene change and working backwards is a bit unusual. But the approach is yielding new insights to tumor cell progression and could define novel molecular targets for treating cancer.

A wave of anti-cancer drugs aimed at molecular targets – like the so-called “leukemia pill” Gleevec – currently is being tested and approved. The Vanderbilt-Ingram scientists are looking for the next round of molecular targets, Matrisian said.

Matrisian described a new era of cancer research and therapy in which tumors will be defined and treated not according to their original tissue location – breast, skin, colon – but instead according to their particular molecular defects – EGF receptor-overexpressed, ras-mutated, APC-mutated, and so on.

“Our approach is a way of using basic science to define and understand these molecular alterations,” she said. “We’re trying to learn enough about the molecular changes to allow us to narrow down what the most important future therapeutic targets will be.”

In studies described in the August issue of Molecular and Cellular Biology, the investigators define signals that participate in the expression of an MMP called stromelysin in mouse skin tumor cells. The cells begin to make stromelysin late in their progression from normal skin cells to malignant, metastatic spindle carcinoma cells.

Crawford, Matrisian and colleagues discovered a signal that appears to be lost in the metastatic cells. In non-invasive skin tumor cells, this “repressor” signal keeps stromelysin off. When the repressor signal is lost, other signals turn on stromelysin production, making the cells able to invade and metastasize. The repressor protein itself might offer advantages as a therapeutic agent for skin cancer, Crawford said.

In a paper in the same journal in February, the researchers reported a signal required for expression of the MMP matrilysin in intestinal tumors. They found that in addition to a well-accepted signal called beta-catenin, another protein signal called PEA3 is required to turn on matrilysin. “We traced backwards from the MMP to discover something that wasn’t known about intestinal cancer,” Crawford said. Both papers challenge the assumptions in the field, he said.

Because MMPs appear to enable tumor cell invasion and metastasis, drugs that block these proteins are being tested as cancer treatments. Though they may slow down cancer progression, MMP blockers are not likely to completely stop or kill existing cancer cells, Matrisian and Crawford said. The hope, they added, is that blocking an earlier step in cancer progression – the signals that turn on MMPs – will lead to better cancer therapies.

“We know from collaborations that these signaling factors are turning on other genes besides MMPs,” Crawford said. “So perhaps by targeting these factors we could turn off a whole group of genes that are required for tumor progression.”

Other collaborators in the two studies include Diana L. Hulboy, Barbara Fingleton, Mark D. Gustavson, Natasza Kurpios, Rebecca A. Wagenaar, and John A. Hassell. The research was supported by the National Institutes of Health.