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Rôle de la neurotensine dans la progression des adénocarcinomes de l’endomètre et de l’ovaire

Abstract : The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), are correlated with tumor cell aggressiveness in most solid tumors, including hormone-dependent cancers. As the endometrium and ovary are also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial and ovarian carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. The TCGA series for ovarian high-grade serous adenocarcinoma and a series of 46 ovarian tissues were also analyzed. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). Our evidence indicated also the presence of a positive correlation between expression of proliferation marker, MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7 %; grade II, 75.3 %; grade III, 81.4 %; p < 0.001) and an inverse correlation with OS ans PFS (p = 0.02 for both). For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (p = 0.003 and p = 0.03, respectively) revealed high MCM6 mRNA Z-scores associated with reduced OS. These associations were absent for Ki-67. No significant correlation between NTSR1 and MCM6 or Ki-67 was found. In ovarian adenocarcinoma, NTS and NTSR1 were detected in 72 % and 74 % of ovarian cancer, respectively. Furthermore, in a large series of high-grade ovarian cancer, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance (p = 0.02). This correlates with experimental results showing the very specific NTSR1 antagonist, SR48692, enhanced the response to carboplatin in ovarian cancer cells and experimental tumors. When SR48692 is combined with carboplatin, a major improvement of platinum-induced DNA damage and cell death, as well as a decrease in tumor growth, was noted. NTSR1 overexpression is a poor prognostic factor in endometrial and ovarian cancer, highlighting the contribution of NTS in cancer progression and its uses as a prognostic marker, and as a potential therapeutic target. The addition of NTSR1 inhibitor in combination with platinum salt-based therapy could improve the response to the drug
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Submitted on : Wednesday, September 5, 2018 - 4:38:08 PM
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  • HAL Id : tel-01868688, version 1


Mikaël Agopiantz. Rôle de la neurotensine dans la progression des adénocarcinomes de l’endomètre et de l’ovaire. Médecine humaine et pathologie. Université de Lorraine, 2018. Français. ⟨NNT : 2018LORR0078⟩. ⟨tel-01868688⟩



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