Cell motility, tissue stiffness, and cancer

If you open a biology textbook, you’ll probably encounter microscope images of single cells, stained and stuck to glass slides. Imaging—and more generally, studying—cells in two dimensions is much easier than in three, not least because a microscope’s focus doesn’t have to be continually adjusted.

But that convenience is not without cost. At the Biophysical Society’s annual meeting in Baltimore, I learned yesterday that some cells behave differently in 3D than they do in 3D. As Denis Wirtz of the Johns Hopkins University pointed out in his talk, the cells that participate in wound healing or metastatic cancer follow 3D paths through 3D tissue. Understanding that behavior is medically important.

Wirtz and his collaborators study focal adhesions (FAs), the dynamic bundles of fibrous proteins that mediate a cell’s mobility and adhesion. In 2D—that is, on a flat surface in a shallow medium—c ells spread out like fried eggs and large FAs form on the cell’s bottom surface.

In a fully 3D medium, however, Wirtz and his group discovered that cells adopt fluid, less flattened shapes and occasionally sprout appendages that resemble an amoeba’s pseudopodia. What’s more, Wirtz couldn’t see any FAs in his 3D-dwelling cells. The various proteins that make up FAs in 2D-dwelling cells still mediate mobility, but they’re spread more or less evenly inside the cell.

Tumor stiffness

In the talk that followed Wirtz’s, Valerie Weaver of the University of California, San Francisco, described her group’s research into the dynamic interplay between tumor cells and their microenvironment. Weaver noted that tumors are stiffer than the healthy tissue that surrounds them. Could stiffness be a prerequisite of tumor growth in addition to being a property of tumors themselves?

Weaver’s group found in 2005 that cancer cells are indeed more malignant in stiff environments. Her group’s more recent work shows why that’s the case.

In general, a cell’s attachment to the extracellular matrix (ECM) is mediated by transmembrane proteins called integrins. Weaver and her team stiffened the ECM by promoting crosslinkng among the ECM’s collagen fibers. Cancer cells responded by invading the stiffened ECM. Significantly, the invasion could be stopped or accelerated by, respectively, inhibiting or promoting integrin’s activity. Weaver speculates that integrin, which is a signaling protein, somehow communicates with cancer genes.

It’s not clear whether integrin or another molecule that mediates a cell’s mechanical properties could become a “drugable target,” to use a pharmacological term. However, cell and tissue stiffness could become reliable predictors of risk and disease progression.

Charles Day