Molecular imaging shows how metastatic cells move

Like "the little engine that could" from children's literature, metastatic cancer cells such as melanoma and fibrosarcoma have the potential to overcome any biochemical strategy designed to impede their migration through the body. Far from offering an inspirational tale, however, this capability poses an ominous threat to the human host.

By directly observing such cells with real-time 3D confocal fluorescent microscopy, Dr. Peter Friedl found in a series of studies since 2003 that none of the approaches he hoped would stop metastasizing cancer in its tracks is fully effective. Though his experiments failed to achieve their ultimate objective, Friedl's results and video images presented at the 2005 Society for Molecular 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," he said. "They possess various mechanisms of escape, which means that no single strategy on its own will effectively defeat them."

Friedl, a professor of dermatology at the University of Wurzburg in Germany, 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 experiments.

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.

The researchers had earlier demonstrated that the cells can no longer travel together when their ability to use or produce integrins is disabled. But that doesn't stop them; they adjust by migrating as individual cells (Cancer Res 2002;62:2125-2130). Additional published work indicates that disabling the metastatic cells' mechanism to employ proteases simply forces them to weave through the collagen rather than cut through it (J Cell Biol 2003;160:267-277).

Individual cells often adopt amoeboid movement that resembles 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.

His group recently discovered that carbohydrates, rather than integrins and other adhesion receptors, can power cellular motility. Their movement was halted only when the cells were denied all adhesion mechanisms.

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