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Wicher G, Roy A, Vaccaro A, Vemuri K, Ramachandran M, Olofsson T, Imbria RN, Belting M, Nilsson G, Dimberg A, Forsberg-Nilsson K
Neurooncol Adv 7 (1) vdaf010 [2025-01-27; online 2025-01-27]
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, characterized by aggressive growth and a dismal prognosis. Interleukin-33 (IL-33) and its receptor ST2 have emerged as regulators of glioma growth, but their exact function in tumorigenesis has not been deciphered. Indeed, previous studies on IL-33 in cancer have yielded somewhat opposing results as to whether it is pro- or anti-tumorigenic. IL-33 expression was assessed in a GBM tissue microarray and public databases. As in vivo models we used orthotopic xenografts of patient-derived GBM cells, and syngenic models with grafted mouse glioma cells. We analyzed the role of IL-33 and its receptor ST2 in nonmalignant cells of the glioma microenvironment and found that IL-33 levels are increased in cells surrounding the tumor. Protein complexes of IL-33 and ST2 are mainly found outside of the tumor core. The IL-33-producing cells consist primarily of oligodendrocytes. To determine the function of IL-33 in the tumor microenvironment, we used mice lacking the ST2 receptor. When glioma cells were grafted to ST2-deficient mouse brains, the resulting tumors exhibited a more invasive growth pattern, and are associated with poorer survival, compared to wild-type mice. Tumors in ST2-deficient hosts are more invasive, with increased expression of extracellular matrix remodeling enzymes and enhanced tumor angiogenesis. Furthermore, the absence of ST2 leads to a more immunosuppressive environment. Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 39931535
DOI 10.1093/noajnl/vdaf010
Crossref 10.1093/noajnl/vdaf010
pmc: PMC11808570
pii: vdaf010