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When cancer metastasizes, cells detach from an initial malignant tumor and form colonies elsewhere in the body that can grow increasingly aggressive and dangerous.
Myriad scientific papers dating back to 1997 show that as tumors grow larger and pack themselves more tightly into a confined space, the resulting compression makes them more likely to metastasize and to exhibit increased survivability, invasiveness, and aggression. Now, research published March 8 in eLife demonstrates in vitro and in mice that a different kind of compression called confined migration, which metastasizing cancer cells experience as they squeeze through narrow blood vessels, can spur different changes that help the cells survive.
It’s a “rather surprising” result, says Romain Levayer, a cell death and cancer researcher at the Pasteur Institute in France who didn’t work on the study, because for noncancerous cells, “compression is usually associated with cell death and apoptosis.”
“Their results are important to the scientific community, pointing out that we need to consider the direct effect of mechanical stimuli on cancer cells not only in the primary site but also at all steps of metastasis in order to develop better therapeutic strategies,” adds Triantafyllos Stylianopoulos, who heads the Cancer Biophysics Laboratory at the University of Cyprus in Greece and who also didn’t participate in the research.
Typically, metastasis is risky for cancer cells. While metastatic cancers are considerably more difficult for clinicians to treat than tumors that stay put, they also become more vulnerable to a cell death mechanism called anoikis, a kind of apoptosis which can occur during transit and is triggered when integrin proteins break and detach from the extracellular matrix. In healthy cells, anoikis occurs to prevent cells from growing in the wrong place.
The “mechanical threat” of confined migration can be a highly mutagenic pressure on cancer cells, study coauthor Gabriel Ichim, a cell death researcher at the University of Lyon in France, tells The Scientist. Indeed, prior research has shown that confined migration alters gene expression and triggers changes in signaling pathways. “Sometimes cancer cells struggle to go through a hole, the nucleus bursts open, and . . . the nucleus will reform. This induces DNA damage and there are plenty of mutations” as a result, Ichim adds. The eLife paper suggests that it’s the process of confined migration of metastasizing cells, not externally-applied mechanical compression of the initial tumor, that induces changes that stave off anoikis and make the cell more likely to survive.
The mouse experiments provide critical evidence that the aggressive in vitro behavior also translates in vivo.
The researchers simulated the confined conditions that a migrating cancer cell might encounter in the body by forcing human breast cancer cells to pass through channels just 3 micrometers wide and then culturing them. The team stained the cells for biomarkers of apoptosis and found that none had been activated, indicating that squeezing through the channel didn’t impact the cells’ viability or ability to proliferate. And when the researchers measured their ability to form colonies under conditions in which cancer cells aren’t anchored to anything and remain vulnerable to the cell death mechanism, they found that the cells that had traversed narrow channels outperformed controls in the first few days after the migration challenge. This suggests that the compressed cells were indeed better at resisting anoikis, though the effect waned over time. Meanwhile, cells from compressed tumors that did not traverse the channels didn’t show any increased resistance to anoikis. Stylianopoulos suggests there’s a possibility that confined migration further progressed the phenotypic changes triggered by primary tumor compression, but that’s not a question that the experiment was designed to answer.
Harvard University oncologist Lance Munn, who didn’t work on the study, writes in an email to The Scientist that these pores are a useful but imperfect and idealized model, as actual confined migration is a longer journey that involves traversing a network of fibers that can be pushed out of the way—he’s curious whether cancer cells forced through a hydrogel matrix would yield the same results.
To look for differences between the squeezed and unsqueezed cells, the researchers sequenced the RNA from control and experimental breast cancer cells and identified a distinct transcriptional profile in the channel-traveled cells that included the upregulation of proteins that inhibit apoptosis. They also conducted a Western blot analysis, which revealed that the cells that underwent confined migration showed epigenetic changes—specifically, histone modifications—that reduced the stiffness of their nuclei, increased their motility, and granted them greater immunity to the immune response.
Typically, immune cells such as natural killer cells and T cells are highly effective at killing cancer cells in the bloodstream. But when these immune cells were cultured alongside migration-challenged or control breast cancer cells, far more of the squeezed cells survived.
After their in vitro experiments, the researchers injected immunodeficient mice with either control or migration-challenged cells. Six weeks later, stained tissue samples revealed that the experimental group had more metastases and less healthy lung tissue, suggesting that the constricted cancer cells were more aggressive and resistant to anoikis, and were therefore more readily able to migrate to and establish themselves in the lungs.
“The mouse experiments provide critical evidence that the aggressive in vitro behavior also translates in vivo,” Ioannis Zervantonakis, a cancer bioengineer at the University of Pittsburgh who didn’t work on the study, tells The Scientist. “However, this mouse model has a number of limitations, as it does not include an adaptive immune system and only the metastatic cascade steps following tumor cell entry in the blood were modeled. Ultimately, this is a major challenge for the field of cancer biomechanics to develop better in vivo models to study in detail the metastatic progression during each step of the metastatic cascade.”
Going forward, Ichim says that it would be informative to follow the activity of single cells in vivo. He also suggests that researchers should test out existing pharmaceuticals that induce anoikis, or other drugs that relax and soften cancer cells that have been compressed, which might reduce the effects of confined migration and make the cells more susceptible to cell death. Meanwhile, Stylianopoulos says he wants to see whether the same phenomenon occurs with other kinds of cancer, such as those of the prostate, colon, and pancreas.
Munn tells The Scientist that cancer mechanobiology is still a poorly understood field that gets little attention, and while he describes the study as “a step in a new direction,” he says that a lot more work is necessary to determine whether the sequence of events that Ichim and his colleagues found carries over to actual tumor invasion and metastasis in humans.
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