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Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.

ABSTRACT: Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting that BTC utilizes SPHK1 to promote lymphatic metastasis. We found that S1P, sphingosine and ceramide precursors such as monohexosyl-ceramide and sphingomyelin, but not ceramide, were significantly increased in BTC compared to normal biliary tract tissue using LC-ESI-MS/MS. Utilizing The Cancer Genome Atlas cohort, we demonstrated that S1P in BTC is generated via de novo pathway and exported via ABCC1. Further, we found that SPHK1 expression positively correlated with factors related to lymphatic metastasis in BTC. Finally, immunohistochemical examination revealed that gallbladder cancer with lymph node metastasis had significantly higher expression of phospho-SPHK1 than that without. Taken together, our data suggest that S1P generated in BTC contributes to lymphatic metastasis.

SUBMITTER: Hirose Y

PROVIDER: S-EPMC6050292 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.

Hirose Yuki Y Nagahashi Masayuki M Katsuta Eriko E Yuza Kizuki K Miura Kohei K Sakata Jun J Kobayashi Takashi T Ichikawa Hiroshi H Shimada Yoshifumi Y Kameyama Hitoshi H McDonald Kerry-Ann KA Takabe Kazuaki K Wakai Toshifumi T

Scientific reports 20180717 1

Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting th ...[more]

PMID: 30018456

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Project description:Lymphatic endothelial cell homeostasis plays important roles in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial infarction (MI). Our results revealed that sphingosine 1-phosphate receptor 1 (S1pr1) expression in cardiac lymphatic endothelial cells (LECs) was sharply changed after MI. It has been shown that S1pr1 tightly controlled LEC functions and homeostasis. We thus hypothesized that lymphatic endothelial S1pr1 might be involved in post-MI cardiac remodeling. We generated LEC-conditional S1pr1 transgenic mice, in which S1pr1 expression was reduced in cardiac LECs. We performed the left anterior descending coronary artery (LAD) ligation operation to induce MI in these mice. Cardiac functions and remodeling were examined by echocardiography analysis and serial histological analysis. Meanwhile, we performed adoptive cell transfer experiments to monitor macrophage trafficking in post-MI myocardium and their draining lymphatic system. Furthermore, in vitro cell culture experiments and mechanism studies were undertaken to uncover the molecular mechanism by which LEC-S1pr1 regulated cardiac inflammation and remodeling after MI. Our results showed that S1pr1 expression significantly decreased in cardiac LECs after MI. Our in vivo experiments showed that the reduced expression of LEC-S1pr1 deteriorated cardiac function and worsened pathological cardiac remodeling after MI. Our further results demonstrated that the reduced expression of LEC-S1pr1 did not influence macrophage infiltration in an early inflammatory phase of MI, but significantly affected macrophages clearance in the later phase of MI via afferent cardiac lymphatics, and thus influenced inflammatory responses and cardiac outcome after MI. Further study showed that S1P/S1pr1 activated ERK signaling pathway and enhanced CCL2 expression, which promoted macrophage trafficking in a paracrine manner. This study reveals that cardiac lymphatic endothelial cells tightly control macrophage trafficking via lymphatic vessels in injured hearts via S1P/S1pr1/ERK/CCL2 pathway and thus regulate post-MI immune modulation and heart repair. This study highlights the importance of cardiac lymphatic vessel system in orchestrating post-MI immune responses and cardiac remodeling by regulating macrophage transit in injured hearts. Our finding implies that a feasible modulation of S1pr1 signaling in LECs might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.

Project description:BackgroundTo assess the predictive value of radiomics for preoperative lymph node metastasis (LMN) in patients with biliary tract cancers (BTCs).MethodsPubMed, Embase, Web of Science, Cochrane Library databases, and four Chinese databases [VIP, CNKI, Wanfang, and China Biomedical Literature Database (CBM)] were searched to identify relevant studies published up to February 10, 2022. Two authors independently screened all publications for eligibility. We included studies that used histopathology as a gold standard and radiomics to evaluate the diagnostic efficacy of LNM in BTCs patients. The quality of the literature was evaluated using the Radiomics Quality Score (RQS) and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and area under the receiver operating characteristic curve (AUC) were calculated to assess the predictive validity of radiomics for lymph node status in patients with BTCs. Spearman correlation coefficients were calculated, and Meta-regression and subgroup analyses were performed to assess the causes of heterogeneity.ResultsSeven studies were included, with 977 patients. The pooled sensitivity, specificity and AUC were 83% [95% confidence interval (CI): 77%, 88%], 78% (95% CI: 71, 84) and 0.88 (95% CI: 0.85, 0.90), respectively. The substantive heterogeneity was observed among the included studies (I 2 = 80%, 95%CI: 58,100). There was no threshold effect seen. Meta-regression showed that tumor site contributed to the heterogeneity of specificity analysis (P < 0.05). Imaging methods, number of patients, combined clinical factors, tumor site, model, population, and published year all played a role in the heterogeneity of the sensitivity analysis (P < 0.05). Subgroup analysis revealed that magnetic resonance imaging (MRI) based radiomics had a higher pooled sensitivity than contrast-computed tomography (CT), whereas the result for pooled specificity was the opposite.ConclusionOur meta-analysis showed that radiomics provided a high level of prognostic value for preoperative LMN in BTCs patients.

Dataset Information

Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.

Publications

Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.

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