Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrastenhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter A Brix by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low A Brix appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between A Brix and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1a) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low A Brix was associated with upregulation of HIF1a protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low A Brix was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance. Cancer Res; 72(20); 5285-95. Ó2012 AACR.

Increasing evidence suggests that fatty acid desaturases, rate-limiting enzymes in unsaturated fatty acid biosynthesis, are important factors in the pathogenesis of lipid-induced insulin resistance. The conversion of dihomogamma linolenic acid (DGLA) into arachidonic acid (AA) in human plasma phospholipids has been shown to be regulated by insulin, suggesting a role for insulin in fatty acid desaturase 1 regulation. However insulin's role in monocyte inflammation associated with obesity and lifestyle disease development is uncertain. We therefore investigated if insulin is able to induce expression of stearoyl-CoA desaturase (SCD, Δ9 desaturase), fatty acid desaturase 1 (FADS1, Δ5 desaturase), and fatty acid desaturase 2 (FADS2, Δ6 desaturase), as well as the sterol regulatory element binding transcription factor 1-c (SREBP-1c) in monocytes. Here, for the first time, we demonstrate that THP-1 monocytes are insulin-responsive in inducing expression of SCD, FADS1, and FADS2 in a time- and dose-dependent manner. Understanding secondary consequences of postprandial hyperinsulinemia may open up new strategies for prevention and/or treatment of obesity-related metabolic complications.

Purpose: We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.Experimental Design: Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.Results: Membranous expression of ectodomain isoforms alone, without the coexpression of the fulllength receptor, showed correlations to poor clinical outcome that were highly significant for lymph nodenegative patients (locoregional control, P ¼ 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P ¼ 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.Conclusion: Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.