Activation of CD95 can have two different outcomes—cell death or cell growth. The mechanism behind this has been unclear until now. Scientists from the German Cancer Research Center (DKFZ) have shown that the impact of CD95 activation depends on whether there are isolated cancer cells or three-dimensional structures. Individual cells are programmed to die following CD95 activation. In contrast, CD95 activation stimulates growth in clusters of cancer cells, for example in solid tumors.
In a paper published today in Cell Reports, senior author Ana Martin-Villalba and her team describe their efforts to understand which factors decide whether CD95 activation leads to cell death or cell growth.
The team collaborated with Motomu Tanaka from the University of Heidelberg to jointly develop artificial cell membranes into which they could insert any amount of the CD95 ligand. Using this method, they discovered that a particular distance between the individual ligand molecules was necessary to achieve ideal activation of CD95—and to actually induce cell death in cells isolated from biopsies of pancreatic cancer or glioblastomas grown in a petri dish.
The researchers then assumed that they had found the perfect way to cause tumor cells in the body to die and extended their experiments to brain tumors in mice. They gave the animals latex beads with the ideal surface density of CD95 ligands. However, instead of observing a reduction in the tumor mass, as expected, the opposite occurred: tumor growth was accelerated. In order to clarify the apparent discrepancy between cell culture and animal experiments, the researchers experimented with tumorspheres. CD95 activation via the artificial cell membrane stimulated growth in these cell spheroids, which behaved like natural tumor tissue.
"The impact of CD95 activation—cell death or growth—appears to depend primarily on whether there are isolated cancer cells, as grown in culture, or cells in three-dimensional structures," Gülce Gülculer, lead author of the paper, explained. Individual cells are programmed to die following CD95 activation. In natural conditions, however, namely in a tissue structure, CD95 activation stimulates growth. In Gülculer's experiments, even contact to a single neighboring cell was enough to protect tumor cells from CD95-induced cell death.