In a study published in the journal Nature Immunology, an international research team led from Karolinska Institutet explain the molecular mechanisms behind how gliobastomas influence the immune system, which causes them to stimulate cancer growth rather than attacking it.
Glioblastomas are one of the most malignant forms of brain tumor and are difficult to surgically remove because the tumor cells invade the surrounding healthy brain tissue. They also affect the microglia in such a way that they stimulate the tumor cells instead of attacking them. The research group has previously shown that pro-inflammatory activation of microglia is controlled by a group of enzymes called caspases. In the present study, they sought to examine if the way the cancer cells affect microglia also includes a similar mechanism. By cultivating microglia and glioblastoma cells together the researchers were able to show that the cancer cells inhibit caspase-3 activity in the microglia.
“We show that it’s the same inhibition of caspase-3 that causes the microglia to stimulate the tumor cells instead of attacking them,” says Bertrand Joseph, Principal Investigator at Karolinska Institutet’s Department of Oncology-Pathology. “When we removed caspase-3 from the microglia in a glioblastoma mouse model the tumors grew more quickly.”
Their results demonstrate that the glioma cells use a nitric oxide-dependent mechanism to force microglia to modify caspase-3 to form a tumor-stimulating form of these cells.
“Two things surprised us,” says Joseph. “First and foremost, that affecting the signaling mechanism between glioblastoma cells and microglia that we discovered has such a major effect on tumor growth. Secondly, that basal caspase-3 activity, which is often considered to be an absence of activity, fulfills an essential function in regulating microglia cell behavior.”
Bertrand Jospeh. Photo: Ulf Sirborn