MR Imaging Distinguishes Tumor Hypoxia Levels of Different Prognostic and Biological Significance in Cervical Cancer
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PROVIDER: PRJNA614472 | ENA |
REPOSITORIES: ENA
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Project description:Tumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences, but are not easily assessable in patients. We present a method based on diagnostic dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) that visualizes a continuous range of hypoxia levels in tumors of cervical cancer patients. Hypoxia images were generated using an established approach based on pixel-wise combination of the DCE-MRI parameters e and Ktrans, reflecting oxygen consumption and supply, respectively. An algorithm to retrieve hypoxia levels from the images was developed and validated in 28 xenograft tumors, by comparing the MRI-defined levels with hypoxia levels derived from pimonidazole stained histological sections. We further established an indicator of hypoxia levels in patient tumors based on expression of nine hypoxia responsive genes. A strong correlation was found between these indicator values and the MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2/M checkpoint were associated with moderate hypoxia, and epithelial-to-mesenchymal transition and inflammatory responses with significantly more severe levels. At the mildest levels, interferon response hallmarks, together with stabilization of HIF1A protein by immunohistochemistry, appearred significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance.
2020-09-01 | GSE147384 | GEO
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Project description:Emerging biomarkers based on medical images and molecular characterization of tumor biopsies open up for combining the two disciplines and exploiting their synergy in treatment planning. We compared pretreatment classification of cervical cancer patients by two previously validated imaging- and gene-based hypoxia biomarkers, evaluated the influence of intratumor heterogeneity, and investigated the benefit of combining them in prediction of treatment failure. The imaging-based biomarker was hypoxic fraction, determined from diagnostic dynamic contrast enhanced (DCE)-MR images. The gene-based biomarker was a hypoxia gene expression signature determined from tumor biopsies. Paired data were available for 118 patients. Intratumor heterogeneity was assessed by variance analysis of MR images and multiple biopsies from the same tumor. The two biomarkers were combined using a dimension-reduction procedure. The biomarkers classified 75% of the tumors with the same hypoxia status. Both intratumor heterogeneity and distribution pattern of hypoxia from imaging were unrelated to inconsistent classification by the two biomarkers, and the hypoxia status of the slice covering the biopsy region was representative of the whole tumor. Hypoxia by genes was independent on tumor cell fraction and showed minor heterogeneity across multiple biopsies in 9 tumors. This suggested that the two biomarkers could contain complementary biological information. Combination of the biomarkers into a composite score led to improved prediction of treatment failure (HR:7.3) compared to imaging (HR:3.8) and genes (HR:3.0) and prognostic impact in multivariate analysis with clinical variables. In conclusion, combining imaging- and gene-based biomarkers enables more precise and informative assessment of hypoxia-related treatment resistance in cervical cancer, independent of intratumor heterogeneity.
2020-06-26 | GSE146114 | GEO
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Project description:Glucocorticoids are primary stress hormones that have been implicated in the pathogenesis of cognitive impairments and psychiatric illnesses. The hippocampus expresses high levels of glucocorticoid (GR) and mineralocorticoid receptors (MR) which both bind glucocorticoids. However, the specific and cooperative roles played by GR and MR in mediating the direct actions of stress on the hippocampus are unknown. To elucidate the function of hippocampal GR and MR, we generated mice with conditional knockout of GR (GREmx1-cre), MR (MREmx1-cre), or both GR and MR (GRMREmx1-cre) in the hippocampus. Genome-wide microarrays were performed on RNA isolated from the whole hippocampus to 1) identify genes subject to regulation by GR alone, MR alone, or both GR and MR and 2) identify the genes responsible for the morphological and behavioral phenotypes observed in these mice.
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Project description:Mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. The differential effects of GR and MR on inflammatory signaling and their contextual dependencies are relevant to the design of next generation drugs with improved safety and efficacy While MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established
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