Glioblastoma microenvironment contains multiple hormonal and non-hormonal growth-stimulating factors

Daniel Dahlberg; Jutta Rummel; Sonia Distante; Gustavo Antonio De Souza; Maria Ekman Stensland; Espen Mariussen; Helge Rootwelt; Øyvind Voie; Bjørnar Hassel

doi:10.1186/s12987-022-00333-z

Glioblastoma microenvironment contains multiple hormonal and non-hormonal growth-stimulating factors

Fluids Barriers CNS. 2022 Jun 4;19(1):45. doi: 10.1186/s12987-022-00333-z.

Authors

Daniel Dahlberg¹, Jutta Rummel², Sonia Distante³, Gustavo Antonio De Souza^{4

5}, Maria Ekman Stensland⁴, Espen Mariussen^{6

7}, Helge Rootwelt³, Øyvind Voie⁶, Bjørnar Hassel^{2

6

8}

Affiliations

¹ Department of Neurosurgery, Oslo University Hospital, Nydalen, PO box 4950, 0424, Oslo, Norway. dandah@ous-hf.no.
² Department of Neurohabilitation and Complex Neurology, Oslo University Hospital, Oslo, Norway.
³ Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
⁴ Institute of Immunology and Centre for Immune Regulation, Oslo University Hospital, Oslo, Norway.
⁵ Department of Biochemistry, Universidade Federal Do Rio Grande Do Norte, Natal, RN, Brazil.
⁶ Norwegian Defence Research Establishment (FFI), Kjeller, Norway.
⁷ Department of Air Quality and Noise, Norwegian Institute of Public Health, Oslo, Norway.
⁸ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Abstract

Background: The growth of malignant tumors is influenced by their microenvironment. Glioblastoma, an aggressive primary brain tumor, may have cysts containing fluid that represents the tumor microenvironment. The aim of this study was to investigate whether the cyst fluid of cystic glioblastomas contains growth-stimulating factors. Identification of such growth factors may pave the way for the development of targeted anti-glioblastoma therapies.

Methods: We performed hormone analysis of cyst fluid from 25 cystic glioblastomas and proteomics analysis of cyst fluid from another 12 cystic glioblastomas.

Results: Glioblastoma cyst fluid contained hormones within wide concentration ranges: Insulin-like growth factor 1 (0-13.7 nmol/L), insulin (1.4-133 pmol/L), erythropoietin (4.7-402 IU/L), growth hormone (0-0.93 µg/L), testosterone (0.2-10.1 nmol/L), estradiol (0-1.0 nmol/L), triiodothyronine (1.0-11.5). Tumor volume correlated with cyst fluid concentrations of growth hormone and testosterone. Survival correlated inversely with cyst fluid concentration of erythropoietin. Several hormones were present at concentrations that have been shown to stimulate glioblastoma growth in vitro. Concentrations of erythropoietin and estradiol (in men) were higher in cyst fluid than in serum, suggesting formation by tumor or brain tissue. Quantitatively, glioblastoma cyst fluid was dominated by serum proteins, illustrating blood-brain barrier leakage. Proteomics identified several proteins that stimulate tumor cell proliferation and invasiveness, others that inhibit apoptosis or mediate adaption to hypoxia and some that induce neovascularization or blood-brain barrier leakage.

Conclusion: The microenvironment of glioblastomas is rich in growth-stimulating factors that may originate from the circulation, the tumor, or the brain. The wide variation in cyst fluid hormone concentrations may differentially influence tumor growth.

Keywords: Cyst fluid; Erythropoietin; Glioblastoma; Growth factors; Insulin-like growth factor; Testosterone.

MeSH terms

Erythropoietin*
Estradiol / analysis
Estradiol / pharmacology
Glioblastoma* / metabolism
Growth Hormone
Humans
Male
Testosterone
Tumor Microenvironment

Substances

Erythropoietin
Testosterone
Estradiol
Growth Hormone