Brain Cancer: Failure of Resolution of Inflammation?

Medulloblastoma therapy, including radiation and chemotherapy, induces cell death resulting in tumor cell debris assumed to be inert or inhibitory to tumor growth. However, tumor cell death (debris) produced by cytotoxic therapy can accelerate tumor progression through the inflammatory response, suggesting that every attempt to kill tumor cells is a double‐edged sword. Inflammation is regulated by endogenous specialized pro‐resolving lipid mediators (SPMs), such as resolvins and protectins, which are present in the brain and CSF. These lipid autacoids stimulate the clearance of cellular debris by macrophages, resulting in reduced localized pro‐inflammatory cytokines. A loss of SPMs is associated with several neurodegenerative diseases but has not been studied in brain cancer. We hypothesize that reduced levels of SPMs correlate with brain cancer progression and that control of tumor cell debris‐mediated inflammation through resolvins and protectins represents a novel approach to brain cancer treatment. Here, we show that SPM receptors are expressed by human brain tumors including glioblastoma and medulloblastoma. Medulloblastoma tumor cell debris generated by front‐line chemotherapy or targeted therapy stimulates primary tumor growth when co‐injected with a subthreshold (non‐tumorigenic) inoculum of tumor cells by triggering the release of pro‐inflammatory cytokines. Stimulation of the resolution of inflammation via protectins and resolvins suppressed orthotopic medulloblastoma. Protectins and resolvins down‐regulated proinflammatory cytokine release in debris‐activated microglia and stimulate the clearance of tumor debris by inducing macrophage phagocytosis of apoptotic tumor cells. Histological analysis of SPM‐treated medulloblastoma and glioblastoma tumors revealed suppressed Ki‐67‐stained tumor cell proliferation. Thus, brain tumor progression results from a loss of resolution of tumor debris‐associated inflammation. Enhancing endogenous clearance of tumor cell debris via protectins and resolvins is a novel biological target to complement current cytotoxic brain cancer therapy and addresses the intrinsic limitation of current cancer therapy involving cell death. Our studies provide a new strategy for the prevention and treatment of therapy‐induced resistance in medulloblastoma and other brain cancers.Support or Funding InformationThis work was supported by the National Cancer Institute grant RO1 01CA170549‐02 (D.P.); ROCA148633‐01A4 (D.P.); and the Credit Unions Kids at Heart Team (D.P.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.