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.

Intravoxel Incoherent Motion Combined With Dynamic Contrast‐Enhanced Perfusion MRI of Early Cervical Carcinoma: Correlations Between Multimodal Parameters and HIF‐1α Expression

“…33 In this study, a low molecular weight contrast agent (Gd-DTPA) was used, which might have some influence on the assessment of the K trans value. Second, HIF-1α expression was observed not only in tumor cells but also in the stromal component of the tumor, 34 but this study observed the HIF-1α expression only in tumor cells, just as in many previous studies. 15,16,20 Therefore, the correlation between multiple imaging parameters and HIF-1α expression in the stromal component of the cervical tumor is unclear and needs to be further investigated.…”

Asparaginase‐like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study

“…The 18 F‐FDG PET/CT images were acquired with a Biograph 40 True Point scanner (Siemens, Erlangen, Germany) using an established protocol . 18 F‐FDG was administered by intravenous injection 60–120 minutes before scanning.…”

Imaging of Preclinical Endometrial Cancer Models for Monitoring Tumor Progression and Response to Targeted Therapy

“…In general, hypoxia leads to a reduced response to chemo-and radiotherapy, and we have shown that imaging and tissue markers for hypoxia predict reduced survival in EC [67]. Therefore, detecting hypoxic tumors by preoperative functional imaging might have therapeutic consequences and improve risk-stratification.…”