By Caperton Gillett

Imagine a garden carefully planted with a number of neatly tended flowers—and one weed. Before long, that one weed has become lots of weeds that have choked out the blooms.

How did the garden become overrun? Why did the weeds appear in the flower garden and not the vegetable garden? Was it something in the soil? Something about the weeds? Something about the flowers, maybe, that made them more weed-prone? How can you keep the weeds from spreading—or prevent them entirely?

Danny Welch, Ph.D., asks himself these questions every day, although his field is more cellular than floral. A senior scientist with UAB’s Comprehensive Cancer Center, the Center for Metabolic Bone Disease, the Cell Adhesion and Matrix Research Center, and the Gene Therapy Center, Welch is a nationally known expert in the biology and genetics of cancer metastasis—the movement of cancer cells from the original tumor to other parts of the body. Through his research, he tries to determine which cancer cells will metastasize, the mechanisms behind the process and how to control it.

“Ninety percent of cancer deaths are directly attributable to metastasis,” making it a crucial topic in cancer research, Welch says. And every scientist is trying to answer the same question: Why do some cancer cells metastasize while others don’t? “Every gram of tumor, which is about the size of a pencil eraser, sheds a million cells into the blood every day,” says Welch. “The more cells that shed into the bloodstream, the more statistically likely that a rare event—that is, a metastasis—will develop.” But he says that some tumors, like melanoma, are highly aggressive, releasing cells that are more likely to take root and grow new tumors, while others, including basal cell carcinomas, rarely spread in that manner.

Solving the mystery of metastasis is an urgent focus for scientists because it may provide new avenues for treatment in cancer’s early stages. “By the time we diagnose a tumor, it’s been shedding cells and seeding the rest of the body for years,” Welch says. “So controlling the behavior of the cells after they’ve left the tumor is a good new option” for stopping the spread of the disease.

Theories on a Trigger

Welch says that scientists have several theories about what triggers metastasis in some of those cells. Genetic mutations may be the cause, or certain microscopic environments may encourage the cells to take root. Some tumors may even be able to “call out” along cellular pathways to locate potential metastatic sites.

“We know that there are sets of genes that turn on and off inappropriately in order for metastasis to take place,” Welch says. “When those genes are disregulated, they affect how the tumor cells interact with other cells.” In an article for the journal The Lancet, Welch notes that cancer cells are more prone to mutation than normal cells, resulting in cells that resist normal growth controls and restraints. For instance, a cell that is not programmed to die, as normal cells are, has a better chance of thriving at another site in the body when it becomes separated from a tumor. A complex cell-growth process known as epithelial-mesenchymal transition (EMT) may also give some cells the ability to become metastatic.

Still other cells may lack genes that would order them not to metastasize. “In my lab, we have been looking at signaling pathways [the biological “circuits” that enable cells to function] that are inappropriately turned off so that we can fix them,” Welch says. “My lab has cloned a bunch of metastasis suppressors. Cells that are able to metastasize don’t have suppressors, and we’re trying to replace those.”

Those suppressors serve a variety of purposes. Some prevent metastasis entirely; others limit it to certain sites in the body. The existence of the suppressors, Welch says, is evidence that the capacity to metastasize is not hardwired into every cancer cell.

Sowing the Seeds

Welch also stresses the importance of the microenvironment where the cells exist. “The microenvironment, in tumor biology, includes everything the cancer cells interact with at any point in time,” he says. “So for a cell in a tumor, the microenvironment is the tumor or the blood vessels, and when it’s moving through the bloodstream, the microenvironment includes whatever the cell interacts with in the blood.”

Some microenvironments are more welcoming than others, Welch says. Blood flow, the existence of certain types of cells or damaged tissue, or organ-specific growth factors expressed through signaling pathways may encourage cells shed from a tumor to take root. Again, genetics may play a role; some genes in cancer cells trigger growth only in specific tissues.

While some “seeds” (tumor cells) will only grow in an appropriate “soil” (tissue microenvironment), Welch says the reverse also is true. Even fully malignant breast cancer cells could revert to normal cells if they land in the right environment, he says. And cancer cells made metastatic by the EMT process may return to a non-metastatic state depending upon their surroundings.

Perhaps most surprising is the discovery that tumors come with a sophisticated search function—they can send out as yet unidentified molecules along signaling pathways to locate prime microenvironments, condition them for metastasis, and release cells to target those areas.

One study showed that signals released by a tumor induced bone marrow cells to home in on specific tissue sites. The cellular clusters, Welch notes in his article, may have provided a “permissive niche” for metastasis—and a target for blocking it. “We are now beginning to decode the language used in the cross talk between tumor cells and their environment, and that could lead to eventual interruption of this dialogue,” he writes.

The Key to Controlling Cancer?

In addition to providing the foundation for new cancer solutions, determining which—and how many—of the millions of cells shed from a tumor will metastasize could change existing treatments as well. Welch writes that while chemotherapy or hormonal therapy reduces the risk of distant metastases by about a third, 70 to 80 percent of breast cancer patients receiving those treatments would have survived without them. In other words, attempting to eliminate all of the shed cells could expose patients to unnecessary amounts of therapeutic agents.

Welch adds that new treatments aimed at disabling the shed cells may offer patients the prospect of a normal, healthy life with less discomfort than traditional treatments. “The hot topic is how to take advantage of what we know and make metastasis a chronic disease as opposed to an acute, deadly one,” Welch says. “There’s a group of about eight or 10 labs in the world that have identified some molecules that control the cells shed by tumors. Those molecules keep the cells under control but don’t eliminate them. And if they’re kept under control, the patient is effectively cured.”

This article originally appeared in the fall 2008 issue of Crossroads, the magazine of the UAB Comprehensive Cancer Center.