Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E-2 and suppress tumor growth in medulloblastoma

Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the omega 3-long chain polyunsaturated fatty acids (omega 3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model.Main methods: Effects of omega 3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography.Key findings: omega 3-LCPUFA decreased prostaglandin E2 (PGE(2)) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE(2) and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All omega 3-LCPUFA and dihomo-gamma-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among omega 3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry.Significance: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment

Endogenous Matrix-Derived Inhibitors of Angiogenesis

Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which can inhibit the angiogenic process. These molecules can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived inhibitors of angiogenesis, such as endostatin, tumstatin, canstatin and arresten, are bioactive fragments of larger ECM molecules. These substances become released upon proteolysis of the ECM and the vascular basement membrane (VBM) by enzymes of the tumor microenvironment. Although the role of matrix-derived angiogenesis inhibitors is well studied in animal models of cancer, their role in human cancers is less established. In this review we discuss the current knowledge about these molecules and their potential use as cancer therapeutics and biomarkers