title: Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer.
abstract: 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.
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.affiliation: Department of Radiology, Haukeland University Hospital, Norway.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Fasmer
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Mauland
authors.affiliation: Department of Radiology, Haukeland University Hospital, Norway.|Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Sigmund
authors.initials: S
authors.lastname: Ytre-Hauge
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Radiology, Haukeland University Hospital, Norway.|Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Husby
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Ingvild L
authors.initials: IL
authors.lastname: Tangen
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Mari K
authors.initials: MK
authors.lastname: Halle
authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Woie
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Bjørge
authors.affiliation: Department of Physics, University of Oslo, Norway.|The Intervention Center, Oslo University Hospital, Norway.
authors.forename: Atle
authors.initials: A
authors.lastname: Bjørnerud
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.|Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Department of Radiology, Haukeland University Hospital, Norway.|Section of Radiology, Department of Clinical Medicine, University of Bergen, Norway.
authors.forename: Ingfrid S
authors.initials: IS
authors.lastname: Haldorsen
mesh_terms: D015415:Biomarkers / Q000032:analysis; D000072645:Cancer-Associated Fibroblasts / Q000502:physiology; D002453:Cell Cycle; D015687:Cell Hypoxia; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000401:mortality; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019788:Fluorodeoxyglucose F18
keywords: FDG-PET/CT; HIF-1α; MRI; endometrial carcinoma; endometrial hyperplasia