Report from SMI: Lessons lurk in resilient metastatic cells

Like the little engine that could from children's literature, metastatic cancer cells such as melanoma or fibrosarcoma have the potential to overcome any single biochemical strategy designed to destroy the mechanisms of locomotion that power their migration through the body. Far from offering an inspiration tale, however, these capabilities pose an ominous threat to the human host.

By directly observing such cells with real-time 3D confocal fluorescent microscopy, Dr. Peter Friedl, a professor of dermatology at the University of Würzburg in Germany, found that none of the approaches he hoped would stop metastasizing cancer in its tracks is fully effective. Though his experiment was a failure, his results and amazing video images presented at the 2005 Society for Molecule Imaging meeting demonstrate how evolution has equipped cancer cells with potent genomic defenses.

"One must expect to be surprised in attempting to develop pharmaceutical strategies designed to inhibit the motility of migrating cancer cells," Friedl said. "They possess various mechanisms of escape, which means that no single strategy on its own will to effectively defeat them."

Friedl and colleagues observed the cancer cells metastasizing as single cells or in strands or sheets of cells hanging together, as they moved through a dense collagen fiber matrix designed for the experiment. Pioneering single cells blaze a trail for the strands by extracting a protease that digests the collagen and integrins for force generation. Cell clumps or sheets also release protease, widening the pathway and allowing more cells to pass.

Friedl demonstrated that when the cells' ability to use or produce integrin is disabled, they can no longer travel together, but that doesn't stop them. They adjust by migrating as individual cells. Disabling their mechanism to employ proteases simply forces them to weave through the collagen rather than cut through it.

Individual cells often adopt amoeboid movement resembling the Dictyostelium slime mold familiar to college biology students. A single cell develops a front amoeboid foot that pulls it along. This is a flexible and robust way to move, Friedl said.

The individual cells draw on genomic resources to elongate themselves to squeeze through spaces as small as two microns.

Carbohydrates power the single cell motility. Only after the cells were denied all adhesion mechanisms - integrins and carbohydrates - was their movement halted.

Imaging study results led Friedl to conclude that a multidrug strategy may be the only means, other than killing the cells, of halting the metastatic behavior. Molecular imaging studies also suggest that matrix metalloproteinases may inadvertently supply these cells with a substance that aids their locomotion.