Cancer Cells Take Advantage of Endothelial Cell Gaps to Metastasize

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Cancer cells may rely on opportunism, as well as chemical signaling, to spread through the body, according to a new study (“Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation”) published in PLOS Computational Biology by mathematicians at the University of Birmingham.

As cancer cells metastasize, they need to cross layers of endothelial cells. It has been thought that the cancer cells signal to the endothelial cells making them open up gaps through which the cancer can migrate. Now a team of researchers in Birmingham have suggested an alternative, or complementary, process may also be at work. Collaborating with partners at MIT, the University of Zaragoza, and others, the team built a detailed mathematical model of the endothelial cells’ behavior to show how and where openings in the endothelial layer appear, and how long they remain open.

Their results showed how the physical forces within the cells’ structure continually push and pull the cells in different directions, sometimes causing the bonds between them to rupture, leaving temporary gaps.

“The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells,” the investigators wrote.

“We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.”
Researchers tested their model on cell cultures of endothelial monolayers with cancer cells, and observed how the cancer cells were able to capitalize on this endothelial movement and migrate through the gaps.

“The gaps in the endothelium open and close spontaneously, whether cancer cells are present or not,” explained lead researcher, Fabian Spill, PhD, lecturer in applied mathematics at the University of Birmingham. “They are caused by an interplay between mechanics and chemistry exerting different forces on the cells. Much work has already been done to characterize the chemistry of the endothelium. Our work complements this research, focusing on the mechanical forces at work in these processes.”

The scientists also found that openings were most likely to appear at the junctions of three or more cells, as opposed to two-cell borders. Cancer cells that had landed on borders between two cells were able to migrate towards these tricellular junctions, where they leaked through. This indicates that the cancer cells are able not only to signal to the endothelium to chemically open new gaps, they can also employ an opportunistic wait-and-see approach. This enables them to take advantage of the spontaneous formation of gaps in the endothelium.

In this study, the team focused on the vascular system. Future work will examine the lymphatic system or different types of endothelial cells, and will also focus in more detail on other contributing factors to endothelial gap dynamics, such as blood flow and the 3D structure of blood vessels, all of which will affect the ability of cancer cells to transmigrate.

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