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Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.

ABSTRACT: Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified that reactive oxygen species (ROS) regulated the adhesive molecules. Intriguingly, attached HCC cells released exosomes containing both SMAD Family Member 3 (SMAD3) protein and mRNA, which were delivered to detached HCC cells and facilitated their adhesion. These exosomes induced enhanced SMAD3 signaling in the recipient HCC cells and increased their adhesive ability. In addition, we showed that SMAD3-abundant exosomes existed in the peripheral blood of patients with HCC, and their levels correlated with disease stage and the SMAD3 expression of primary tumors. Our study suggested a possible mechanism by which primary HCC supported metastases formation and revealed the role of SMAD3 in the exosomes-mediated crosstalk between primary and circulating HCC cells.

SUBMITTER: Fu Q

PROVIDER: S-EPMC6250679 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.

Fu Qihan Q Zhang Qi Q Lou Yu Y Yang Jiaqi J Nie Gang G Chen Qi Q Chen Yiwen Y Zhang Jingying J Wang Jianxin J Wei Tao T Qin Hao H Dang Xiaowei X Bai Xueli X Liang Tingbo T

Oncogene 20180710 47

Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified th ...[more]

PMID: 29991801

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Project description:The genome?wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome?wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty?three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F?FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three?color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and ??defensin genes, which are significantly associated with anti?angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.

Dataset Information

Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.

Publications

Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.

Similar Datasets

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