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Exosomal TGF-?1 is correlated with lymphatic metastasis of gastric cancers.

ABSTRACT: Exosomes are nano-vesicles transporting bioactive material between cells. This study explored the prognostic association of exosomal TGF-?1 with lymph node (LN) metastasis of gastric cancer (GC). TGF-?1 expressions in the exosomes isolated from the gastroepiploic veins of 61 GC patients analyzed by ELISA. The regulatory T (Treg) cells in celiac LNs of gastric cancer analyzed by immunohistochemistry. Exosomal TGF-?1 expression and the ratio of Treg cells in draining LNs were both significantly associated with pathological stages and LN metastasis of gastric cancer. Besides, the exosomal TGF-?1 expression and Treg proportion in LN were also significantly correlated in gastric cancer patients. Recombinant TGF-?1 and exosomes isolated from GC patients were used to induce FOXP3+ Treg cells from naïve T cells in vitro. Compared to the control, recombinant TGF-?1 induced more CD25 (41%), FOXP3 (19%) and CTLA-4 (47%), while reduced CD45RA expression by 38% in primary naïve T cell cultures (p<0.01). Exosomes treatment induced more CD25 and 45% higher CTLA-4 expression, and increased 29% higher of CD45RA-negative cells than recombinant TGF-?1 did (p<0.01). Adding TGF-?1 neutralizing antibody partially abrogated the effects of exosomes on Treg induction. Our study showed exosomal TGF-?1 related to lymph node metastasis and the ratio of Treg cells in lymph nodes of gastric cancers. Exosomes from gastric cancer patients could induce Treg cells formation through the effect of TGF-?1.

SUBMITTER: Yen EY

PROVIDER: S-EPMC5714749 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Exosomal TGF-β1 is correlated with lymphatic metastasis of gastric cancers.

Yen Er-Yen EY Miaw Shi-Chuen SC Yu Jhang-Sian JS Lai I-Rue IR

American journal of cancer research 20171101 11

Exosomes are nano-vesicles transporting bioactive material between cells. This study explored the prognostic association of exosomal TGF-β1 with lymph node (LN) metastasis of gastric cancer (GC). TGF-β1 expressions in the exosomes isolated from the gastroepiploic veins of 61 GC patients analyzed by ELISA. The regulatory T (Treg) cells in celiac LNs of gastric cancer analyzed by immunohistochemistry. Exosomal TGF-β1 expression and the ratio of Treg cells in draining LNs were both significantly as ...[more]

PMID: 29218244

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Project description:BackgroundPatients with lymph node (LN) metastatic bladder cancer (BCa) present with extremely poor prognosis. BCa-derived exosomes function as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome-mediated LN metastasis in BCa are unclear.MethodsWe conducted the high-throughput sequencing to explore the expression profile of long noncoding RNA (lncRNA) in urinary exosomes (urinary-EXO) from patients with BCa and further evaluated the clinical relevance of exosomal lncRNA BCYRN1 in a larger 210-case cohort. The functional role of exosomal BCYRN1 was evaluated through the migration and tube formation assays in vitro and the footpad-popliteal LN metastasis model in vivo. RNA pull-down assays, luciferase assays, and actinomycin assays were conducted to detect the regulatory mechanism of exosomal BCYRN1.ResultsLncRNA BCYRN1 was substantially upregulated in urinary-EXO from patients with BCa, and associated with the LN metastasis of BCa. We demonstrated that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1-associated H3K4 trimethylation in WNT5A promoter, which activated Wnt/β-catenin signaling to facilitate the secretion of VEGF-C in BCa. Moreover, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and thus formed an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 significantly impaired exosomal BCYRN1-induced the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively associated with the shorter survival of BCa patients and identified as a poor prognostic factor of patients.ConclusionOur results uncover a novel mechanism by which exosomal BCYRN1 synergistically enhances VEGF-C/VEGFR3 signaling-induced lymphatic metastasis of BCa, indicating that BCYRN1 may serve as an encouraging therapeutic target for patients with BCa.

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Exosomal TGF-?1 is correlated with lymphatic metastasis of gastric cancers.

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Exosomal TGF-β1 is correlated with lymphatic metastasis of gastric cancers.

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