PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages
Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we est...
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| Veröffentlicht in: | Laboratory investigation 2021-03, Vol.101 (3), p.353-368 |
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| creator | Sakamoto, Hiroki Koma, Yu-ichiro Higashino, Nobuhide Kodama, Takayuki Tanigawa, Kohei Shimizu, Masaki Fujikawa, Masataka Nishio, Mari Shigeoka, Manabu Kakeji, Yoshihiro Yokozaki, Hiroshi |
| description | Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy.
The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy. |
| doi_str_mv | 10.1038/s41374-020-00512-2 |
| format | Article |
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The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.</description><identifier>ISSN: 0023-6837</identifier><identifier>EISSN: 1530-0307</identifier><identifier>DOI: 10.1038/s41374-020-00512-2</identifier><identifier>PMID: 33311557</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>13/1 ; 13/21 ; 13/51 ; 13/89 ; 38/61 ; 38/77 ; 631/67/1504/1477 ; 631/67/327 ; 692/420/755 ; 82/80 ; 96/63 ; 96/95 ; Aged ; AKT protein ; Bone marrow ; Cancer ; Cancer-Associated Fibroblasts - metabolism ; Cell Line, Tumor ; Cell Movement - drug effects ; Cells, Cultured ; DNA microarrays ; Esophageal cancer ; Esophageal Neoplasms - metabolism ; Esophageal Squamous Cell Carcinoma - metabolism ; Esophagus ; Female ; Fibroblast activation protein ; Fibroblasts ; Gene expression ; Humans ; Immunohistochemistry ; Inhibitors ; Laboratory Medicine ; Leukocyte migration ; Macrophages ; Macrophages - drug effects ; Macrophages - physiology ; Male ; Medicine ; Medicine & Public Health ; Mesenchyme ; Microenvironments ; Middle Aged ; Monoculture ; Neoplasm Invasiveness ; Pathology ; Plasminogen Activator Inhibitor 1 - metabolism ; Plasminogen Activator Inhibitor 1 - pharmacology ; Plasminogen activator inhibitors ; Prognosis ; Proteins ; Receptor density ; Receptors ; Squamous cell carcinoma ; Stem cells</subject><ispartof>Laboratory investigation, 2021-03, Vol.101 (3), p.353-368</ispartof><rights>2020 The Authors</rights><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c721t-205b732e52db2534aaa1e28ef0008ab7ec366d74e3f10ba5610164441721f8e93</citedby><cites>FETCH-LOGICAL-c721t-205b732e52db2534aaa1e28ef0008ab7ec366d74e3f10ba5610164441721f8e93</cites><orcidid>0000-0002-3022-8466 ; 0000-0002-6518-5574 ; 0000-0002-7413-0751 ; 0000-0001-5276-3331</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33311557$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sakamoto, Hiroki</creatorcontrib><creatorcontrib>Koma, Yu-ichiro</creatorcontrib><creatorcontrib>Higashino, Nobuhide</creatorcontrib><creatorcontrib>Kodama, Takayuki</creatorcontrib><creatorcontrib>Tanigawa, Kohei</creatorcontrib><creatorcontrib>Shimizu, Masaki</creatorcontrib><creatorcontrib>Fujikawa, Masataka</creatorcontrib><creatorcontrib>Nishio, Mari</creatorcontrib><creatorcontrib>Shigeoka, Manabu</creatorcontrib><creatorcontrib>Kakeji, Yoshihiro</creatorcontrib><creatorcontrib>Yokozaki, Hiroshi</creatorcontrib><title>PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages</title><title>Laboratory investigation</title><addtitle>Lab Invest</addtitle><addtitle>Lab Invest</addtitle><description>Cancer-associated fibroblasts (CAFs) contribute to the progression of various cancers. Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy.
The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.</description><subject>13/1</subject><subject>13/21</subject><subject>13/51</subject><subject>13/89</subject><subject>38/61</subject><subject>38/77</subject><subject>631/67/1504/1477</subject><subject>631/67/327</subject><subject>692/420/755</subject><subject>82/80</subject><subject>96/63</subject><subject>96/95</subject><subject>Aged</subject><subject>AKT protein</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Cells, Cultured</subject><subject>DNA microarrays</subject><subject>Esophageal cancer</subject><subject>Esophageal Neoplasms - metabolism</subject><subject>Esophageal Squamous Cell Carcinoma - metabolism</subject><subject>Esophagus</subject><subject>Female</subject><subject>Fibroblast activation protein</subject><subject>Fibroblasts</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inhibitors</subject><subject>Laboratory Medicine</subject><subject>Leukocyte migration</subject><subject>Macrophages</subject><subject>Macrophages - 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Previously, we reported the significance of CAFs in esophageal squamous cell carcinoma (ESCC); however, the functions of CAFs in the ESCC microenvironment remain unknown. To investigate CAFs' function, we established an indirect coculture assay between human bone marrow-derived mesenchymal stem cells (MSCs) and ESCC cells. Cocultured MSCs expressed more fibroblast activation protein, one of the markers of CAFs, compared with monocultured MSCs. Therefore, we defined cocultured MSCs as CAF-like cells. To identify molecules associated with the ESCC progression in CAFs, we conducted a cDNA microarray analysis on monocultured MSCs and CAF-like cells to compare their gene expression profiles. We found that SERPINE1, which encodes plasminogen activator inhibitor-1 (PAI-1), was more abundant in CAF-like cells than in monocultured MSCs, and the PAI-1 derived from CAF-like cells induced the abilities of migration and invasion in both ESCC cells and macrophages by the Akt and Erk1/2 signaling pathways via the low-density lipoprotein receptor-related protein 1 (LRP1), which is a PAI-1 receptor. Based on immunohistochemistry assays of ESCC tissues, higher expression levels of PAI-1 and LRP1 were correlated with poor prognosis in ESCC patients. These results suggest that the PAI-1/LRP1 axis contributes to the progression of ESCC, making it a potential target for ESCC therapy.
The authors show that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts promotes the invasion of esophageal squamous cell carcinoma (ESCC) cells and the migration of macrophages via lipoprotein receptor-related protein 1 (LRP1). High expression of PAI-1 and/or LRP1 is associated with poor prognosis in patients with ESCC, and the PAI-1/LRP1 axis could be a target of anticancer therapy.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>33311557</pmid><doi>10.1038/s41374-020-00512-2</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-3022-8466</orcidid><orcidid>https://orcid.org/0000-0002-6518-5574</orcidid><orcidid>https://orcid.org/0000-0002-7413-0751</orcidid><orcidid>https://orcid.org/0000-0001-5276-3331</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Laboratory investigation, 2021-03, Vol.101 (3), p.353-368 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7892342 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | 13/1 13/21 13/51 13/89 38/61 38/77 631/67/1504/1477 631/67/327 692/420/755 82/80 96/63 96/95 Aged AKT protein Bone marrow Cancer Cancer-Associated Fibroblasts - metabolism Cell Line, Tumor Cell Movement - drug effects Cells, Cultured DNA microarrays Esophageal cancer Esophageal Neoplasms - metabolism Esophageal Squamous Cell Carcinoma - metabolism Esophagus Female Fibroblast activation protein Fibroblasts Gene expression Humans Immunohistochemistry Inhibitors Laboratory Medicine Leukocyte migration Macrophages Macrophages - drug effects Macrophages - physiology Male Medicine Medicine & Public Health Mesenchyme Microenvironments Middle Aged Monoculture Neoplasm Invasiveness Pathology Plasminogen Activator Inhibitor 1 - metabolism Plasminogen Activator Inhibitor 1 - pharmacology Plasminogen activator inhibitors Prognosis Proteins Receptor density Receptors Squamous cell carcinoma Stem cells |
| title | PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T03%3A37%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PAI-1%20derived%20from%20cancer-associated%20fibroblasts%20in%20esophageal%20squamous%20cell%20carcinoma%20promotes%20the%20invasion%20of%20cancer%20cells%20and%20the%20migration%20of%20macrophages&rft.jtitle=Laboratory%20investigation&rft.au=Sakamoto,%20Hiroki&rft.date=2021-03-01&rft.volume=101&rft.issue=3&rft.spage=353&rft.epage=368&rft.pages=353-368&rft.issn=0023-6837&rft.eissn=1530-0307&rft_id=info:doi/10.1038/s41374-020-00512-2&rft_dat=%3Cproquest_pubme%3E2470030068%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2490885951&rft_id=info:pmid/33311557&rft_els_id=S0023683722003002&rfr_iscdi=true |