Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer
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Anna Berg1,2, Kristine E. Fasmer3, Karen K. Mauland1,2, Sigmund Ytre-Hauge3,4, Erling A. Hoivik1,2, Jenny A. Husby3,4, Ingvild L. Tangen1,2, Jone Trovik1,2, Mari K. Halle1,2, Kathrine Woie2, Line Bjørge1,2, Atle Bjørnerud5,6, Helga B. Salvesen1,2, Henrica M. J. Werner1,2, Camilla Krakstad2,7,*, Ingfrid S. Haldorsen3,4,*
1Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway
2Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway
3Department of Radiology, Haukeland University Hospital, Norway
4Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway
5Department of Physics, University of Oslo, Norway
6The Intervention Center, Oslo University Hospital, Norway
7Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Norway
*These authors contributed equally to this work
Anna Berg, email: [email protected]
Keywords: endometrial carcinoma, endometrial hyperplasia, HIF-1α, MRI, FDG-PET/CT
Received: July 02, 2016 Accepted: September 04, 2016 Published: September 13, 2016
Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.
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