By Sean Henahan, Access Excellence

TORONTO - The discovery of the gene that encodes a protein that enables cancer cells to spread throughout the body could lead to treatments that would stop cancer in its tracks, reported scientists from the U.S. National Cancer Institute at the annual meeting of the American Association for Cancer Research.

Researchers have purified and cloned the gene for autotaxin, one of a small family of proteins known as ectozymes that are believed vital to tumor cell motility. The protein stimulates tumor cells to "crawl" from one body site to another, reported Lance Liotta, M.D., Ph.D., chief of NCI's Laboratory of Pathology.

"The field of ectoenzymes is increasingly recognized as an important avenue of research, which may have a role in tumor cell biology, " Dr. Liotta said. "Our particular interest is in a handful of proteins that stimulate motility of cancer cells to other sites in the body. The resulting migration and spread of these cells (metastasis) is usually what kills the cancer patient."

NCI scientists hypothesize that autotaxin, a powerful member of the family of autocrine motility factor proteins identified by Dr. Liotta's lab in 1988, may play a role in the initiation of the metastatic cascade.

The spread of cancer cells from a local tumor site to tissues throughout the body is known as metastases. The process of metastases involves a multi-step cascade of events during which renegade tumor cells overwhelm normal immune defenses and gain access to multiple tissues throughout the body. When tumor cells metastisize, they leave the primary tumor and burrow through a blood vessel or a vessel in the lymphatic system, and then travel back into another tissue. Cytokines and components of the extracellular matrix appear to influence the speed of metastases.

"We believe that autotaxin's role, though not fully under stood, is to set tumor cells in motion by stimulating cell crawling away from the primary tumor site to a future metastatic location," noted Dr. Mary L. Stracke, also at NCI.

Autotaxin induces tumor cells to extend "pseudopodia" or sensors at the leading edge of the cell. The pseudopodia contain a number of receptors that act as the tumor cell's eyes, guiding it to its destination -- attachment to the basement membrane (a physical barrier that separates tissue compartments) and an integral step in the cell's long journey in and out of the circulatory system on the way to a secondary site. The pseudopodia tip also contains degradative enzymes which can cut protein barriers in front of the invading tumor cell, she explained.

Cellular migration is not limited to cancer metastasis, it also plays an essential role in normal processes such as embryo development and wound-healing. Whether autotaxin is a normal protein involved in these processes, or one that mutates during malignancy is not yet known. Autotaxin was first isolated in human melanoma cells and has also been found in several other types of cancer cells.

The next stage of research will involve determining which part of autotaxin is responsible for stimulating motility. The researchers also plan to look for it in other cancer cells, as well as normal cells.

For more information on this area of research, see: Liotta, L., et al. Proc. Natl. Acad. Sci. 83, 3302-3306, 1986; Stracke, M., et al. Jour. Biol. Chem. 267, 2524-2529, 1992; Murata, J., et al. Jour. Biol. Chem. 269, 30479-30484, 1994.