Abstract
Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR1) as well as ferritin heavy (FTH) and light (FTL) chain in astrocytic brain tumors. A cohort of 111 astrocytic brain tumors (grade II-IV) was stained immunohistochemically with antibodies against TfR1, FTH, and FTL and scored semi-quantitatively. Double-immunofluorescence stainings were established to determine the phenotype of cells expressing these markers. We found that TfR1, FTH, and FTL were expressed by tumor cells in all grades. TfR1 increased with grade (p<0.001), but was not associated with prognosis in the individual grades. FTH and FTL were expressed by tumor cells and cells with microglial/macrophage morphology. Neither FTH nor FTL increased with malignancy grade, but low FTH expression by both tumor cells (p = 0.03) and microglia/macrophages (p = 0.01) correlated with shorter survival in patients anaplastic astrocytoma. FTL-positive microglia/macrophages were frequent in glioblastomas, and high FTL levels correlated with shorter survival in the whole cohort (p = 0.01) and in patients with anaplastic astrocytoma (p = 0.02). Double-immunofluorescence showed that TfR1, FTH, and FTL were co-expressed to a limited extent with the stem cell-related marker CD133. FTH and FTL were also co-expressed by IBA-1-positive microglia/macrophages. In conclusion, TfR1 was highly expressed in glioblastomas and associated with shorter survival in the whole cohort, but not in the individual malignancy grades. Low levels of FTH-positive tumor cells and microglia/macrophages were associated with poor survival in anaplastic astrocytomas, while high amounts of FTL-positive microglia/macrophages had a negative prognostic value. The results suggest that regulation of the iron metabolism in astrocytic brain tumors is complex involving both autocrine and paracrine signaling.
Highlights
Astrocytic brain tumors are the most frequent and aggressive brain tumors in adults [1]
transferrin receptor-1 (TfR1) expression was predominantly seen in GBMs, and high TfR1 expression was associated with worse prognosis analyzing all astrocytic brain tumors together
Analyzing the the Cancer Genome Atlas (TCGA) and the National Cancer Institute REpository for Molecular BRAin Neoplastic Data (NCI REMBRANDT) datasets, high TfR1 levels were found correlate with shorter overall survival in patients with glioma, and similar results were found when investigating protein expression data from grade II-IV tissue microarrays (TMAs) [20]
Summary
Astrocytic brain tumors are the most frequent and aggressive brain tumors in adults [1]. The most common and aggressive type is the glioblastoma (GBM) having a median survival of 15 months [2, 3]. Tumor cells in GBM display a cellular hierarchy with brain tumor-initiating cells (BTIC) at the apex [4, 5]. BTIC are located in niches and thrive in stressful conditions such as hypoxia, inflammation, oxidative stress, and low supply of glucose [6,7,8,9,10]. Iron metabolism is thought to be involved in mechanisms supporting these conditions [11,12,13]. Deregulation of the iron homeostasis has been linked to other cancers as well as neuro-degenerative diseases [14]
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