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Stromal and tumor cell responses to hypoxia and treatment within the glioma microenvironment

Author

Summary, in English

Glioblastoma is the most aggressive primary brain tumor in adults. Despite treatment, tumors invariably recur, and the recurring tumor is resistant to therapies. New approaches are needed for the successful treatment of glioblastoma patients.
Tumors are not simply a compilation of molecularly and phenotypically identical neoplastic cells. Instead, the tumor-associated stroma is instrumental in supporting tumor growth. Moreover, the cancer cells themselves are highly plastic, with some of the cells exhibiting stem-like phenotypes. Cancer stemness is linked to more aggressive disease, recurrence, and worse patient outcomes in several cancers. Hypoxic signaling, mediated by the HIF transcription factors, is a cornerstone in the maintenance of cancer stemness in glioblastoma and other cancers.
The aim of this thesis was to evaluate how microenvironmental cues affect the interactions between the tumor microenvironment and glioma stem-like cells in glioblastoma. We addressed how treatments and hypoxia affect tumor-associated astrocytes in ways that consequently alter glioma cell properties, and how hypoxia and pseudo-hypoxia are involved in stemness maintenance in glioblastoma. For this work, we used genetically engineered mouse models of glioma, primary stromal and glioma cell lines, classical glioblastoma cell lines, and organotypic slice cultures. We evaluated cell stemness by using multiple functional assays in combination with stem cell marker expression analysis. In papers I and II, we investigated the response of astrocytes to extrinsic factors of the microenvironment, namely radiation and temozolomide treatment, and to intrinsic factors of the microenvironment, namely intermediate and severe hypoxia. Astrocytes became reactive in response to these cues and produced extracellular matrix that altered glioma cell properties, including stemness. In papers III and IV, we investigated the role of hypoxia and pseudo-hypoxia in the maintenance of aggressive glioma phenotypes. We showed that the generation of the cleaved form of the cell surface glycoprotein CD44 leads to the stabilization of the HIFs in the perivascular and the perinecrotic glioma niche, leading to increased hypoxic signaling and glioma cell stemness. Moreover, we showed that p75NTR signaling is involved in the activation of the hypoxic signaling pathway and is also regulating glioma cell stemness and migration in hypoxia.
All in all, this thesis elucidated aspects of the glioblastoma microenvironment, namely irradiated and hypoxic astrocytes, and the CD44 and p75NTR signaling, that can lead to the development of new targeted therapeutic strategies.

Publishing year

2021

Language

English

Publication/Series

Lund University, Faculty of Medicine Doctoral Dissertation Series

Issue

2021:108

Document type

Dissertation

Publisher

Lund University, Faculty of Medicine

Topic

  • Cancer and Oncology

Keywords

  • Cancer
  • glioblastoma
  • tumor microenvironment
  • reactive astrocytes
  • hypoxia
  • CD44
  • p75NTR

Status

Published

Research group

  • Brain Tumor Biology

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-8021-115-4

Defence date

29 October 2021

Defence time

09:00

Defence place

Stora Hörsalen, Medicon Village, Scheelevägen 2 i Lund

Opponent

  • Margareta Wilhelm (docent)