Tumor cells kill epithelial cells to escape and metastasize

Scientists have wondered exactly how cancer cells in the blood stream penetrate the vascular wall and go on to metastasize elsewhere. A new study now shows that tumor cells breach the endothelial-cell barrier by inducing endothelial cells to die, which creates an opening to allow the tumor cells to escape, according to an article published online August 3, 2016 in Nature.

This necroptosis of endothelial cells occurs with the aid of a molecule called death receptor 6 (DR6). The investigators also showed that inhibiting this mechanism reduced tumor-cell-induced endothelial necroptosis, tumor cell extravasation, and metastasis.

Metastasis is the leading cause of cancer-related death in humans, a process in which individual tumor cells spread through the circulatory system to reach distant organs. But tumor cells’ metastatic potential heavily depends on a way to pass through the endothelial-cell barrier and escape from the blood stream.

In this study, investigators in Germany sought to understand exactly how this mechanism worked on a molecular level. Through in vitro experiments, the researchers observed that tumor cells induce programmed necrosis of endothelial cells. For this mechanism to occur, the tumor cells express amyloid precursor protein (APP), which joins and activates its receptor, DR6, already present on the surface of the endothelial cells of the vascular wall.

“This marks the start of the cancer cells’ attack on the vascular wall, which culminates in the necroptosis of wall cells,” explained the study’s first author Boris Strilic, PhD, postdoctoral researcher at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany.

“We were then able to show in studies on mice that the same process occurs in living organisms,” Dr. Strilic noted.

Next, the researchers tested genetically-modified mice whose DR6 was deleted, and found that less endothelial cell necroptosis and less metastasis occurred in these mice. “This effect was also found after a blockade of DR6 or the cancer-cell protein APP, thus confirming our previous observations,” Dr. Strilic said.

The researchers have yet to determine whether the tumor cells migrate directly through the resulting gap in the vascular wall or whether an indirect effect in the neighboring cells around the dead endothelial cell causes a gap to form. “We have evidence that many more molecules are released when the vascular wall cell dies and that they render the surrounding area more permeable to cancer cells,” said lead investigator Stefan Offermanns, MD, Director of the Department of Pharmacology at the Max Planck Institute.

“This mechanism could be a promising starting point for treatments to prevent the formation of metastases,” Dr. Offermanns suggested.

But first, more research is needed to determine whether blocking DR6 will trigger unwanted side effects, and also whether these results can be transferred to humans.