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Hypoxia‐Inducible Exosomes Facilitate Liver‐Tropic Premetastatic Niche in Colorectal Cancer

Hao SunKey Laboratory of Environmental Medicine Engineering,Ministry of Education,School of Public Health,Southeast University,Nanjing,ChinaQingtao MengBeijing Key Laboratory of Environmental Toxicology,School of Public Health,Capital Medical University,Beijing,ChinaChengyu ShiHepatobiliary Center,The First Affiliated Hospital of Nanjing Medical University,Nanjing,ChinaHongbao YangCenter for Drug Safety Evaluation and Research,China Pharmaceutical University,Nanjing,ChinaXiaobo LiKey Laboratory of Environmental Medicine Engineering,Ministry of Education,School of Public Health,Southeast University,Nanjing,ChinaShenshen WuBeijing Key Laboratory of Environmental Toxicology,School of Public Health,Capital Medical University,Beijing,ChinaGiuseppe FamiliariLaboratory of Electron Microscopy “Pietro Motta,”,SAIMLAL Department,Faculty of Pharmacy and Medicine,Sapienza University of Rome,Rome,ItalyMichela RelucentiLaboratory of Electron Microscopy “Pietro Motta,”,SAIMLAL Department,Faculty of Pharmacy and Medicine,Sapienza University of Rome,Rome,ItalyMichael AschnerDepartment of Molecular Pharmacology,Albert Einstein College of Medicine,Bronx,NYXuehao WangHepatobiliary Center,The First Affiliated Hospital of Nanjing Medical University,Nanjing,ChinaRui ChenBeijing Key Laboratory of Environmental Toxicology,School of Public Health,Capital Medical University,Beijing,China

2021en

ABI

Аннотация

BACKGROUND AND AIMS: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. APPROACH AND RESULTS: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30-TNF receptor-associated factor 2-p65-mediated immunosuppression signaling also contributed to this process. CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.

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DOI: 10.1002/hep.32009

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