2-oxoglutarate dependent dioxygenases; HIF-1; HIF-hydroxylase; VEGF; glioblastoma multiforme; glioma; vitamin C; Oncology; Cancer Research
Abstract :
[en] Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF transcription factors are regulated at the post-translation level via HIF-hydroxylases. These hydroxylases require oxygen and 2-oxoglutarate as substrates, and ferrous iron and ascorbate as cofactors. In this retrospective observational study, we aimed to determine whether ascorbate played a role in the hypoxic response of glioblastoma, and whether this affected patient outcome. We measured the ascorbate content and members of the HIF-pathway of clinical glioblastoma samples, and assessed their association with clinicopathological features and patient survival. In 37 samples (37 patients), median ascorbate content was 7.6 μg ascorbate/100 mg tissue, range 0.8 - 20.4 μg ascorbate/100 mg tissue. In tumours with above median ascorbate content, HIF-pathway activity as a whole was significantly suppressed (p = 0.005), and several members of the pathway showed decreased expression (carbonic anhydrase-9 and glucose transporter-1, both p < 0.01). Patients with either lower tumour HIF-pathway activity or higher tumour ascorbate content survived significantly longer than patients with higher HIF-pathway or lower ascorbate levels (p = 0.011, p = 0.043, respectively). Median survival for the low HIF-pathway score group was 362 days compared to 203 days for the high HIF-pathway score group, and median survival for the above median ascorbate group was 390 days, compared to the below median ascorbate group with 219 days. The apparent survival advantage associated with higher tumour ascorbate was more prominent for the first 8 months following surgery. These associations are promising, suggesting an important role for ascorbate-regulated HIF-pathway activity in glioblastoma that may impact on patient survival.
Disciplines :
Oncology
Author, co-author :
Burgess, Eleanor R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Crake, Rebekah ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Phillips, Elisabeth; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Morrin, Helen R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand ; Cancer Society Tissue Bank, University of Otago Christchurch, Christchurch, New Zealand
Royds, Janice A; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Slatter, Tania L; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Wiggins, George A R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Vissers, Margreet C M; Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Robinson, Bridget A; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand ; Canterbury Regional Cancer and Haematology Service, Canterbury District Health Board, and Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
Dachs, Gabi U; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Language :
English
Title :
Increased Ascorbate Content of Glioblastoma Is Associated With a Suppressed Hypoxic Response and Improved Patient Survival.
Funding was obtained from the Canterbury Medical Research Foundation, the University of Otago Research Grant and the Mackenzie Charitable Foundation.We would like to thank the patients who gifted their brain tumours to research, the Cancer Society Tissue Bank for collecting the samples, and the University of Otago for the doctoral scholarship for EB. We are grateful to Dr Juliet Pullar for expertise with ascorbate analysis by HPLC-ECD. We thank Associate Professor John Pearson (biostatistician, University of Otago, Christchurch) for his statistical advice.
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