Cheng Zhang1, Jing Yang1, Yang Chen1, Jing Gao2, Fangli Jiang1, Haiyan Liao2, Xiang Liu3, Yuan Wang3, Guanyi Kong3, Xiaotian Zhang1, Jian Li1, Lin Shen4. 1. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China. 2. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China. 3. Department of R&D, Echo Biotech Co., Ltd, Beijing, People's Republic of China. 4. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China. shenlin@bjmu.edu.cn.
Abstract
BACKGROUND: Peritoneum, liver and lymph node are the most common metastatic sites of gastric cancer (GC). Biomarkers for GC's organo-tropic metastasis remained largely unknown, which was investigated in this study from the perspective of small extracellular vesicle (sEV)-derived miRNAs. METHODS: Plasma from treatment-naïve GC patients including no metastasis (M0), peritoneal metastasis (PM), hepatic metastasis (HM) and distant lymph node metastasis (dLNM)) were divided into one discovery (N = 40), one training (N = 40) and one validating cohort (N = 86), then assessed by sEV-miRNA-sequencing and sEV-miRNA-qPCR. Functional explorations were also performed for verification. RESULTS: The expression profiles of sEV-miRNAs varied greatly across different metastatic patterns. Based on logistic regression models, we constructed signatures for M0 (hsa-miR-186-5p/hsa-miR-200c-3p/hsa-miR-429/hsa-miR-5187-5p/hsa-miR-548ae-5p), PM (hsa-miR-200c-3p/hsa-miR-429), HM (hsa-miR-200c-3p/hsa-miR-429) and dLNM (hsa-miR-324-5p/hsa-miR-374a-5p/hsa-miR-429/hsa-miR-548ae-5p). These signatures vigorously characterized organo-tropic metastasis (all displaying AUC > 0.8, consistency ≥ 75%), and effectively conjectured the risk of future metastasis within 5 years (accuracy 45.5% for occurrence, 70% for organotropism, P = 0.002 for prognostic diversity). Additionally, we explored these seven biomarker miRNAs' impact on GC's in vitro motility and discussed their potential involvement in cancer-related biological processes and pathways. CONCLUSIONS: Our work highlighted that plasma sEV-miRNAs powerfully characterized and predicted the organo-tropic metastasis of GC and provided new insight into the applications of sEV-based liquid biopsy in clinical practice.
BACKGROUND: Peritoneum, liver and lymph node are the most common metastatic sites of gastric cancer (GC). Biomarkers for GC's organo-tropic metastasis remained largely unknown, which was investigated in this study from the perspective of small extracellular vesicle (sEV)-derived miRNAs. METHODS: Plasma from treatment-naïve GC patients including no metastasis (M0), peritoneal metastasis (PM), hepatic metastasis (HM) and distant lymph node metastasis (dLNM)) were divided into one discovery (N = 40), one training (N = 40) and one validating cohort (N = 86), then assessed by sEV-miRNA-sequencing and sEV-miRNA-qPCR. Functional explorations were also performed for verification. RESULTS: The expression profiles of sEV-miRNAs varied greatly across different metastatic patterns. Based on logistic regression models, we constructed signatures for M0 (hsa-miR-186-5p/hsa-miR-200c-3p/hsa-miR-429/hsa-miR-5187-5p/hsa-miR-548ae-5p), PM (hsa-miR-200c-3p/hsa-miR-429), HM (hsa-miR-200c-3p/hsa-miR-429) and dLNM (hsa-miR-324-5p/hsa-miR-374a-5p/hsa-miR-429/hsa-miR-548ae-5p). These signatures vigorously characterized organo-tropic metastasis (all displaying AUC > 0.8, consistency ≥ 75%), and effectively conjectured the risk of future metastasis within 5 years (accuracy 45.5% for occurrence, 70% for organotropism, P = 0.002 for prognostic diversity). Additionally, we explored these seven biomarker miRNAs' impact on GC's in vitro motility and discussed their potential involvement in cancer-related biological processes and pathways. CONCLUSIONS: Our work highlighted that plasma sEV-miRNAs powerfully characterized and predicted the organo-tropic metastasis of GC and provided new insight into the applications of sEV-based liquid biopsy in clinical practice.
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