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Exosomal microRNA in peritoneal fluid as a biomarker of peritoneal metastases from gastric cancer.

ABSTRACT: Aim:Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum. Methods:Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasis (PM) and comprehensive miRNA expression analysis was carried out. Expressions of candidate miRNAs were then validated in all 58 samples using TaqMan Advanced miRNA Assays. Results:In initial screening, we carried out comprehensive analysis of exosomal miRNA using peritoneal fluids from 11 and 14 patients with or without PM, respectively, and identified 11 dysregulated miRNAs in PM (+) samples. Validation analysis showed that four miRNAs (miR-21-5p, miR-92a-3p, miR-223-3p, and miR-342-3p) were significantly upregulated in 12 PM (+) samples, and their expression levels showed positive correlation with peritoneal cancer index. In contrast, miR-29 family were all downregulated in patients with PM (+) samples. Moreover, in 24 patients with pT4 tumor, miR-29 at gastrectomy tended to be lower in six patients with peritoneal recurrence with significant differences in miR-29b-3p (P = .012). Conclusion:Expression pattern of miRNAs in peritoneal exosomes well reflects the tumor burden in the peritoneal cavity and could be a useful biomarker in the treatment of PM.

SUBMITTER: Ohzawa H

PROVIDER: S-EPMC6992685 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Exosomal microRNA in peritoneal fluid as a biomarker of peritoneal metastases from gastric cancer.

Ohzawa Hideyuki H Kumagai Yuko Y Yamaguchi Hironori H Miyato Hideyo H Sakuma Yasunaru Y Horie Hisanaga H Hosoya Yoshinori Y Kawarai Lefor Alan A Sata Naohiro N Kitayama Joji J

Annals of gastroenterological surgery 20191106 1

<h4>Aim</h4>Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum.<h4>Methods</h4>Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasi ...[more]

PMID: 32021962

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Project description:BackgroundGastric cancer (GC) that metastasizes to the peritoneum is fatal. CF33 and its genetically modified derivatives show cancer selectivity and oncolytic potency against various solid tumors. CF33-hNIS and CF33-hNIS-antiPDL1 have entered phase I trials for intratumoral and intravenous treatments of unresectable solid tumors (NCT05346484) and triple-negative breast cancer (NCT05081492). Here, we investigated the antitumor activity of CF33-oncolytic viruses (OVs) against GC and CF33-hNIS-antiPDL1 in the intraperitoneal (IP) treatment of GC peritoneal metastases (GCPM).MethodsWe infected six human GC cell lines AGS, MKN-45, MKN-74, KATO III, SNU-1, and SNU-16 with CF33, CF33-GFP, or CF33-hNIS-antiPDL1 at various multiplicities of infection (0.01, 0.1, 1.0, and 10.0), and performed viral proliferation and cytotoxicity assays. We used immunofluorescence imaging and flow cytometric analysis to verify virus-encoded gene expression. We evaluated the antitumor activity of CF33-hNIS-antiPDL1 following IP treatment (3×105 pfu × 3 doses) in an SNU-16 human tumor xenograft model using non-invasive bioluminescence imaging.ResultsCF33-OVs showed dose-dependent infection, replication, and killing of both diffuse and intestinal subtypes of human GC cell lines. Immunofluorescence imaging showed virus-encoded GFP, hNIS, and anti-PD-L1 antibody scFv expression in CF33-OV-infected GC cells. We confirmed GC cell surface PD-L1 blockade by virus-encoded anti-PD-L1 scFv using flow cytometry. In the xenograft model, CF33-hNIS-antiPDL1 (IP; 3×105 pfu × 3 doses) treatment significantly reduced peritoneal tumors (p<0.0001), decreased amount of ascites (62.5% PBS vs 25% CF33-hNIS-antiPDL1) and prolonged animal survival. At day 91, seven out of eight mice were alive in the virus-treated group versus one out of eight in the control group (p<0.01).ConclusionsOur results show that CF33-OVs can deliver functional proteins and demonstrate effective antitumor activity in GCPM models when delivered intraperitoneally. These preclinical results will inform the design of future peritoneal-directed therapy in GCPM patients.

Dataset Information

Exosomal microRNA in peritoneal fluid as a biomarker of peritoneal metastases from gastric cancer.

Publications

Exosomal microRNA in peritoneal fluid as a biomarker of peritoneal metastases from gastric cancer.

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