Scientists have discovered a new way to kill the treatment-resistant cancer stem cells that lead to the disease’s spread and recurrence.
In a new paper published by Nature Communications on November 4, Marcus Peter, medicine: hematology/oncology, reveals that cancer stem cells (CSCs) are specifically targeted by a form of cell death discovered earlier this year.
DICE, or cell death induced by CD95 receptor or ligand elimination, is a seemingly counterintuitive approach in which the gene CD95 or its binding ligand CD95L is removed from cancer cells.
It’s considered counterintuitive because CD95L plays a crucial role in helping the immune system kill potentially cancerous cells by infiltrating them and initiating a type of cell death known as apoptosis. Peter, however, discovered that CD95 is also required for cancer cells to survive — which is not the case for healthy normal cells, meaning the gene can be removed without harm.
“When we did this we observed that the death caused by eliminating either CD95 or CD95L is much more profound and much more complete than what occurs when we stimulate CD95 to induce apoptosis,” says Peter, a member of the Robert H. Lurie Comprehensive Cancer Center.
Scientists also discovered that DICE is most efficiently induced in deadly cancer stem cell populations. CSCs are tumor-causing cancer cells that possess characteristics similar to normal stem cells, specifically the ability to give rise to all cell types within a particular cancer.
“When cancer develops resistance to traditional treatments like chemotherapy, it becomes more and more aggressive, in part because of an increased number of cancer stem cells,” Peter says. “This subpopulation of cancer cells, which is most addicted to CD95 for survival, is obliterated by DICE.”
While chemotherapy is effective in killing cancer cells, in part through induction of apoptosis, in most solid cancers, patients eventually stop responding to treatment. The cancer cells that remain are resistant to apoptosis.
“That is where we believe DICE can be most utilized, in collaboration with chemotherapy,” Peter says.
Because cancer cells are more easily killed by apoptosis, whereas cancer stem cells are more vulnerable to DICE, Peter believes treatment can be maximized with the induction of both cell death mechanisms.
“We are trying to figure out how we can convince all of these cells to kill themselves,” Peter says. “If our attempts to convert DICE into a new therapy are successful, it might limit the amount of chemotherapy that is needed, reducing some of the negative side effects.”
Peter has successfully demonstrated an ability to eliminate CSCs using DICE in an animal model of human breast cancer and will next conduct preclinical trials in mice to determine if chemotherapy increases the number of CSCs, as is thought, and if DICE can then be triggered in vivo to eliminate them.