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POSTED 14 NOV 2002


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  One of cancer's best-kept mysteries is locomotion: How do cancer cells move about? What explains the tumor cell's dreaded ability to crank up the engine and drive off to another part of the body?

The life-threatening problem with most cancers occurs when they migrate from the initial siteIt is, after all, metastasis that makes many cancers dangerous. "The real, life-threatening problem with most cancers is that they migrate away from the initial site," says Richard Anderson, a UW-Madison pharmacology professor. "If we could regulate a cell's ability to move in a selective way, we may be able to block cancer metastasis."

Anderson has just filled in one of the blanks in the quest to understand -- and eventually halt -- metastasis.

A starting point for understanding the complicated protein interaction is the extracellular matrix, a fibrous material surrounding all non-blood cells. (Collagen is one familiar example.)

Moving cells, whether healthy or cancerous, grab the extracellular matrix with tiny feet, called focal adhesion complexes. These feet extend inside the cell membrane to a soup of proteins and enzymes with names too hideous for polite conversation.

A disk of regular cells in normal tissue, and a smear of cells in abnormal tissue. Normal, organized breast cells on left. Disorganized cells of breast tumor on right.

Doin' the locomotion
When the locomotive system is working, cells can grab, claw or swim their way along the extracellular matrix. Once cancer cells reach a vein or artery, then take a long-distance trip through the body.

At the far end of the journey, the metastatic cell must escape from the blood vessel, and use the same hand-over-hand method to find a suitable location for further growth.

This process explains, for example, how lung- or breast-cancer cells can spread to the bone.

Whether the traveler is a cancer cell, an immune cell going to fight infection, or a skin cell healing a wound, the movement technique is much the same, says Anderson. "Every single one depends on cell motility through essentially the same mechanism." Indeed, the same focal adhesion system is used in fruit flies, indicating an ancient evolutionary lineage.

An intense blob of blue, round cells, predominates in center of picture, against a cloudy background.
A bone-marrow biopsy of a metastatic growth in bone marrow. Note excess growth of immature cells. U.S. Department of Veterans' Affairs

Got my high-heeled sneakers
Anderson's study (performed in dishes, not in animals), contributed to the emerging picture of cell motility by describing the role of an enzyme we'll call pip kinase. This compound, formally type 1-gamma phosphatidylinositol phosphate kinase (phew!), turns out to be necessary for the assembly of focal adhesion molecules - the high-heeled sneakers of cells on the move.

Pip-kinase interacts with a protein called FAK, which was already known to be involved in metastasis. "FAK works together with pip kinase to assemble focal adhesions. FAK regulates pip kinase and vice versa," says Anderson. "It's really a collaboration."

It's worse than that, if you really need to understand what's going on, because pip kinase has other upstream and downstream effects. But here's the key from a practical (treatment) point of view. Cell mobility is important for wound healing and immune reactions, so it may be unsafe to prevent movement entirely. cancer cell sits on couchHowever, if it's possible to selectively block cell movement in tumors, it may be possible to steal the car keys from the cancer cells.

"Without pip-kinase, you have no focal adhesions, and the cell cannot crawl," says Anderson. "Without pip kinase, the cancer cells would be couch potatoes."

-- David Tenenbaum


Type 1-gamma Phosphatidylinositol Phosphate Kinase Targets and Regulates Focal Adhesions, Kun Ling et al, Nature, 7 Nov. 2002, pp. 89 ff.


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