{"doi":"10.1126/sciadv.abo5525","title":"Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms","abstract":"Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.","journal":"Science Advances","year":2022,"id":250140,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9631,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":334239,"name":"Misako Sato","orcid":"0000-0003-0593-7305","position":1,"is_corresponding":false},{"id":482402,"name":"Hideto Yuasa","orcid":"0000-0003-3979-6213","position":2,"is_corresponding":false},{"id":659587,"name":"Tsutomu Matsubara","orcid":"0000-0003-1100-1052","position":3,"is_corresponding":false},{"id":334241,"name":"Lê Thị Thanh Thủy","orcid":"0000-0003-4460-735X","position":4,"is_corresponding":false},{"id":891622,"name":"Hiroko Ikenaga","orcid":"0000-0001-8952-5353","position":5,"is_corresponding":false},{"id":891623,"name":"Minh Phuong Dong","orcid":"0000-0002-4639-9075","position":6,"is_corresponding":false},{"id":891624,"name":"Ngo Vinh Hanh","orcid":"0000-0003-2656-9249","position":7,"is_corresponding":false},{"id":891625,"name":"Vu Ngoc Hieu","orcid":"0000-0001-7877-3001","position":8,"is_corresponding":false},{"id":891626,"name":"Dinh Viet Hoang","orcid":"0000-0001-7844-3192","position":9,"is_corresponding":false},{"id":891627,"name":"Hoang Hai","orcid":"0000-0001-5607-0794","position":10,"is_corresponding":false},{"id":891628,"name":"Yoshinori Okina","orcid":"0000-0002-9306-2176","position":11,"is_corresponding":false},{"id":334245,"name":"Masaru Enomoto","orcid":"0000-0002-4028-4381","position":12,"is_corresponding":false},{"id":891629,"name":"Akihiro Tamori","orcid":"0000-0001-9119-4864","position":13,"is_corresponding":false},{"id":891630,"name":"Atsuko Daikoku","orcid":"0000-0002-3513-803X","position":14,"is_corresponding":false},{"id":891631,"name":"Hayato Urushima","orcid":"0000-0003-1040-399X","position":15,"is_corresponding":false},{"id":891632,"name":"Kazuo Ikeda","orcid":"0000-0003-2401-969X","position":16,"is_corresponding":false},{"id":891633,"name":"Ninh Quoc Dat","orcid":"0000-0002-8500-4910","position":17,"is_corresponding":false},{"id":607008,"name":"Yutaka Yasui","orcid":"0000-0002-6117-4990","position":18,"is_corresponding":false},{"id":891634,"name":"Hiroji Shinkawa","orcid":"0000-0002-0164-2414","position":19,"is_corresponding":false},{"id":891635,"name":"Shoji Kubo","orcid":"0000-0002-4353-8033","position":20,"is_corresponding":false},{"id":891636,"name":"Ryota Yamagishi","orcid":"0000-0002-6827-2382","position":21,"is_corresponding":false},{"id":891637,"name":"Naoko Ohtani","orcid":"0000-0001-8934-0797","position":22,"is_corresponding":false},{"id":891638,"name":"Katsutoshi Yoshizato","orcid":"0000-0003-2133-7983","position":23,"is_corresponding":false},{"id":891639,"name":"Jordi Gracia‐Sancho","orcid":"0000-0001-7736-4089","position":24,"is_corresponding":false},{"id":334248,"name":"Norifumi Kawada","orcid":"0000-0002-6392-8311","position":25,"is_corresponding":false},{"id":891621,"name":"Truong Huu Hoang","orcid":"0000-0001-9515-9230","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:24:28.242323Z","pmid":"36170363","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}