Ferritin in glioblastoma

Heidi Jaksch-Bogensperger,Peter Eckl,Sabine Spiegl-Kreinecker,Rahman Al-Schameri,Yvonne Ebner,Peter Strasser,Nikolaus Bresgen,Stefan Golaszewski,Serge Weis,Paolo Arosio

doi:10.1038/s41416-020-0808-8

Abstract

Elevated levels of serum ferritin (SF) are observed in several types of cancer; however, little is known on the association between ferritin and glioma, the most frequent type of human primary brain tumour. Here we report that GBM patients show significantly increased pre-surgical SF levels (i.e. ferritinaemia) within the SF reference range and a marked ferritin immunoreactivity of resected tumour tissue. Our findings account for an indirect association between ferritin synthesis in glioma-tissue and altered SF levels, which limits the clinical value of SF as a tumour marker in glioma. Importantly, we show for the first time that GBM-derived glioma cells release ferritin in vitro, which exerts an apoptosis-stimulating activity. Albeit the pathophysiologic context of apoptosis induction by a tumour-derived ferritin remains to be defined, our findings account for a distinct growth-regulatory role of these ferritin species in tumour biology.

Highlights

IntroductionA 450-kDa multimeric iron-storage protein, built from 24 heavy (FTH) and light (FTL) chains, is essential to cellular iron homoeostasis by regulating the intracellularlabileiron pool via its ferroxidase activity conferred by the FTH chain.[1] In the brain, FTHrich isoferritins predominate in neurons and oligodendrocytes, FTL-rich isoferritins in microglial cells and astrocytes in the corpus striatum.[2] Serum ferritin (SF) levels are normally low, but may rise in diseased states, including cancer, leading to malignancy-associated ferritinaemia.[1,3] Tumour cell-based ferritin release (e.g. neuroblastoma) is considered to be causal to rising SF levels, but other sources (e.g. cells of the tumour-surrounding stroma) have been discussed.[1] Still, the clinical and pathophysiological significance of ferritin in cancer is poorly defined, which holds true for glial tumours
Ferritin, a 450-kDa multimeric iron-storage protein, built from 24 heavy (FTH) and light (FTL) chains, is essential to cellular iron homoeostasis by regulating the intracellularlabileiron pool via its ferroxidase activity conferred by the FTH chain.[1]
Our findings strongly support the assumption that glial tumours synthesise and secrete ferritin,[4,6] which is causal to GBMassociated ferritinaemia

Summary

Introduction

A 450-kDa multimeric iron-storage protein, built from 24 heavy (FTH) and light (FTL) chains, is essential to cellular iron homoeostasis by regulating the intracellularlabileiron pool via its ferroxidase activity conferred by the FTH chain.[1] In the brain, FTHrich isoferritins predominate in neurons and oligodendrocytes, FTL-rich isoferritins in microglial cells and astrocytes in the corpus striatum.[2] Serum ferritin (SF) levels are normally low, but may rise in diseased states, including cancer, leading to malignancy-associated ferritinaemia.[1,3] Tumour cell-based ferritin release (e.g. neuroblastoma) is considered to be causal to rising SF levels, but other sources (e.g. cells of the tumour-surrounding stroma) have been discussed.[1] Still, the clinical and pathophysiological significance of ferritin in cancer is poorly defined, which holds true for glial tumours. Three studies have assessed ferritinaemia in gliomas by routine laboratory diagnostics comprising a total number of less than 60 patients,[4,5,6] the biological background of glioma-associated ferritinaemia remaining elusive. We provide evidence for an upregulated ferritin synthesis in glioma tissue, which is not directly associated with elevated SF levels. We show for the first time that tumour-derived ferritins are capable of stimulating apoptosis

Methods

Results

Conclusion