Proteins seem to stop tumor cells from spreading through blood vessels

Researchers have identified a specialized protein that appears to help prevent tumor cells from entering the bloodstream and spreading to other parts of the body.

“We have found that this protein, TRPM7, senses the pressure of circulating fluid and prevents cells from spreading through the vascular system,” said Kaustav Bera, a doctoral student at Johns Hopkins University. candidate in chemical and biomolecular engineering and lead author of the study, which was carried out with colleagues from the University of Alberta and the Universitat Pompeu Fabra.

“We found that metastatic tumor cells have markedly reduced levels of this sensory protein, and that is why they efficiently enter the circulation rather than diverting from the flow of fluid,” said Bera.

The conclusions, published in Scientists progress, help shed light on an unrecognized part of metastasis called intravasation, when cancer cells that have separated from a primary tumor enter the circulation to travel to other parts of the body and establish colonies .

The researchers further show that the artificial increase in the expression of TRPM7 in tumor cells can help stop intravasation – and ultimately metastasis – in its tracks.

TRPM7 has long been known to regulate calcium in cells, but this new understanding of its role in cell migration is exciting, the researchers say. “The process is similar to what happens when you touch a hot kettle, feel it hot and remove your hand,” said lead study author Konstantinos Konstantopoulos, professor of chemical and biomolecular engineering and member of the Johns Hopkins Kimmel Cancer Center.

The protein senses the flow of fluid in the circulatory system and instructs the cell to reverse direction, thereby inhibiting intravasation, he said.

As a rule, the cells of the human body, for example, muscle cells, fat cells and epithelial cells, remain contained in their respective regions. The main exception is blood cells, which patrol the body to fight pathogens. And then there are the cancer cells, which have mutations that allow them to travel and spread.

It is at this stage of the spread that cancer becomes much more dangerous. “Many people will be diagnosed with a primary tumor, but as long as this tumor is contained, surgery can save the person,” said Christopher Yankaskas, senior author and former member of the Konstantopoulos lab, who is now a scientist at Thermo Fisher. . Scientist.

For their initial experiment, the researchers observed healthy fibroblast cells moving through microchannels arranged perpendicularly in a ladder configuration in which fluid could be controlled. When these cells encountered channels where fluid was moving, they would reverse their direction in response to the shear stress exerted by the flow. However, when the cells encountered channels where the fluid was not moving, they entered them.

The researchers then used a process known as RNA interference to prevent cells from expressing TRPM7. What they observed was striking, they say. When this sensor protein was turned off, healthy cells no longer reversed direction in response to the flow. “Imagine then picking up the kettle with an oven mitt, which reduces your sensitivity to heat,” Konstantopoulos said.

In later experiments, researchers found that normal cells had higher levels of TRPM7 than sarcoma cells (a type of cancerous tumor cells), and that artificial expression of the protein in tumor cells increased their sensitivity. to fluid flow.

When normal cells reverse their direction of migration, they avoid exposure to shear stress, but tumor cells do not, Konstantopoulos explained. “Tumor cells are less sensitive, which is why they continue to enter the circulatory system.”

“The goal was to see if we could take these cancer cells and make them behave like normal cells,” Bera said. “And we managed to do it.”

A separate analysis of data from human patients showed that people with osteosarcoma, breast cancer, stomach cancer and liver who expressed high levels of TRPM7 were more likely to live longer than those with higher levels. low in protein.

More research is needed, but the team is hopeful that the findings could eventually lead to new cancer therapies using the activation of CRISPR, an emerging and exciting DNA editing tool.

“We will need further development before we can apply this in a clinical setting, but we believe to provide, for the first time, a definitive picture of the role of TRPM7 in a crucial stage of tumor metastasis,” Konstantopoulos said.