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Lack of ST2 aggravates glioma invasiveness, vascular abnormality, and immune suppression

Wicher, Grzegorz ; Roy, Ananya ; Vaccaro, Alessandra ; Vemuri, Kalyani ; Ramachandran, Mohanraj ; Olofsson, Tommie ; Imbria, Rebeca Noemi ; Belting, Mattias LU ; Nilsson, Gunnar and Dimberg, Anna , et al. (2025) In Neuro-Oncology Advances 7(1).
Abstract

Background. 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. Methods. 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. Results. We analyzed the role of IL-33 and its receptor ST2 in nonmalignant cells of the... (More)

Background. 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. Methods. 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. Results. 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. Conclusions. Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.

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publication status
published
subject
in
Neuro-Oncology Advances
volume
7
issue
1
article number
vdaf010
publisher
Oxford University Press
external identifiers
  • pmid:39931535
  • scopus:85217904746
DOI
10.1093/noajnl/vdaf010
language
English
LU publication?
yes
id
c0335c07-a368-43d6-a7ad-994ae244eb78
date added to LUP
2025-07-03 11:14:23
date last changed
2025-07-04 03:00:03
@article{c0335c07-a368-43d6-a7ad-994ae244eb78,
  abstract     = {{<p>Background. 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. Methods. 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. Results. 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. Conclusions. Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.</p>}},
  author       = {{Wicher, Grzegorz and Roy, Ananya and Vaccaro, Alessandra and Vemuri, Kalyani and Ramachandran, Mohanraj and Olofsson, Tommie and Imbria, Rebeca Noemi and Belting, Mattias and Nilsson, Gunnar and Dimberg, Anna and Forsberg-Nilsson, Karin}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Oxford University Press}},
  series       = {{Neuro-Oncology Advances}},
  title        = {{Lack of ST2 aggravates glioma invasiveness, vascular abnormality, and immune suppression}},
  url          = {{http://dx.doi.org/10.1093/noajnl/vdaf010}},
  doi          = {{10.1093/noajnl/vdaf010}},
  volume       = {{7}},
  year         = {{2025}},
}