A new study published today in the journal Cell Reports by scientists at the German Cancer Research Center (DKFZ) shows that the direction taken by a cancer cell depends on the configuration of the cell itself as well as the activation of a universal cancer cell receptor called CD95. If the cell is isolated, receptor activation causes it to die. On the other hand, if the cell is part of a 3D cluster, activation of CD95 stimulates growth of the tumor. The discovery could be manipulated to help target this growth signal to mean cell death instead, by altering cell conditions.
Cancer cell and lymphocytes. Image Credit: Juan Gaertner / Shutterstock
CD95 is a cell surface protein receptor found on all cancer cells. Acting rather like tiny receivers, its activation occurs when it binds its specific ligand, called C95L. Once this happens, says researcher Ana Martin-Villalba, “We found that CD95 activation usually stimulates tumor growth under natural conditions.” On the other hand, binding with CD95L also induces caspase-mediated apoptosis in some cancer cells. Thus, it can be a promoter or a preventive for cancer cell growth.
Martin-Villalba should know. She has been studying the actions of CD95 for years, and indeed, discovered how it enhanced tumor growth in the malignant brain tumor called glioblastoma.
Now scientists are looking into how this property of CD95 can be exploited to cause cancer cell death without harming neighbouring healthy cells. Earlier studies showed that using CD95L to hit cancer cells backfired seriously, because it induced cell death in liver cells instead. Moreover, most cancer cells do not respond to CD95 activation by apoptosis.
The study and its findings
The current study took the path of exploring the cell growth factors that determine the destiny of the cell following CD95 activation.
A collaborative research team worked to produce artificial cell membranes so that they could create customized CD95L concentrations on the cell surface model. They examined its binding with the CD95 receptor and found a specific separation distance between ligands that resulted in the optimal activation of CD95, and caused the death of isolated cells from pancreatic cancer or glioblastoma in culture.
Excited by this finding, the researchers went on to apply the same conditions to kill cancer cells in a mouse model of brain tumor. They treated the ill mice with latex beads coated with CD95 at the right distance they had discovered. The only problem was with the outcome: rather than shrinking the tumor, the beads promoted tumor growth!
This paradoxical result spurred the scientists on to further experimentation with objects called tumorspheres – very small tumors grown in cultures rather than in animals. When they activated CD95 receptors using the artificial cell membrane with CD95L, they found that these tiny balls of cells behaved like the brain tumors – they grew very fast.
The conclusion they arrived at was that the effect of CD95L binding and activation of CD95 depends first and foremost on the cell surroundings. If the cell is isolated, it dies. If it is part of a tumor, it proliferates. In fact, the experimenters found that if a cell was in contact with just one other cell, CD95 activation failed to induce cell death.
As a result of these striking results, says Martin-Villalba, new techniques can now be brought into play to make CD95 activation spell death rather than growth for tumor cells, and to keep them from developing resistance to therapeutic agents. The study is important in solving the puzzle as to how the same receptor can have such opposing effects.
An earlier phase 2 trial in patients with advanced glioblastomas has proved that CD95 inhibition along with radiation therapy could improve survival. The inhibition was accomplished with a chemical that was developed by a team of which Martin-Villalba formed a key player. However, the current study does a little more to show exactly why CD95 suppression worked. Such findings play a crucial role in helping to identify targets within this signaling system to stop cancer growth.
3D Cellular Architecture Modulates Tyrosine Kinase Activity, Thereby Switching CD95-Mediated Apoptosis to Survival Gülcüler Balta, Gülce S. et al. Cell Reports, Volume 29, Issue 8, 2295 - 2306.e6, https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31368-3