Inhibition of lymphangiogenesis‐related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270
Based on a previous report on the effect of a matrix metalloproteinase (MMP) inhibitory compound, MMI270, in regulating tumor‐induced angiogenesis, as well as recent findings concerning functional correlations among tumor metastasis, angiogenesis and lymphangiogenesis, we investigated the anti‐metas...
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| creator | Nakamura, Eliane Shizuka Koizumi, Keiichi Kobayashi, Mitsuo Saiki, Ikuo |
| description | Based on a previous report on the effect of a matrix metalloproteinase (MMP) inhibitory compound, MMI270, in regulating tumor‐induced angiogenesis, as well as recent findings concerning functional correlations among tumor metastasis, angiogenesis and lymphangiogenesis, we investigated the anti‐metastatic efficacy of MMI270 in a murine model of lymph node metastasis of lung cancer, and analyzed whether this inhibitor could also regulate lymphangiogenesis‐related properties of murine lymphatic endothelial cells (LECs) and invasive properties of Lewis lung cancer (LLC) cells. The observation that MMI270 led to a significant decrease in the weight of tumor‐metastasized lymph nodes of mice led us to test its anti‐lymphangiogenic and anti‐invasive effects in vitro. Murine LECs were characterized by an in vitro tube formation assay, by semi‐quantitative RT‐PCR assay to examine the expression of mRNAs for flt‐4, Flk‐1, Tie‐1, Tie‐2, CD54/ICAM1, vWF, MMPs and uPA, and by western blotting to confirm the protein expression of flt‐4 and CD31/PECAM. This is the first report on the expression of MMP‐2, MMP‐9 and MT1‐MMP in murine LECs, as well as on the inhibition of their enzymatic activity, and of the invasive ability and tube‐forming property of LECs by an MMP inhibitor. Furthermore, MMI270 was shown to strongly inhibit the activity of MMP‐2 and ‐9 produced by LLC cells and the invasion of these cells through Matrigel. In summary, the present results indicate that MMI270, apart from its anti‐tumor angio‐genic application, might be useful as an anti‐metastatic drug, on the basis of its downregulatation of both the lymphangiogenesis‐related properties of LECs and the invasive properties of LLC cells in vitro. (Cancer Sci 2004; 95: 25–31) |
| doi_str_mv | 10.1111/j.1349-7006.2004.tb03166.x |
| format | Article |
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The observation that MMI270 led to a significant decrease in the weight of tumor‐metastasized lymph nodes of mice led us to test its anti‐lymphangiogenic and anti‐invasive effects in vitro. Murine LECs were characterized by an in vitro tube formation assay, by semi‐quantitative RT‐PCR assay to examine the expression of mRNAs for flt‐4, Flk‐1, Tie‐1, Tie‐2, CD54/ICAM1, vWF, MMPs and uPA, and by western blotting to confirm the protein expression of flt‐4 and CD31/PECAM. This is the first report on the expression of MMP‐2, MMP‐9 and MT1‐MMP in murine LECs, as well as on the inhibition of their enzymatic activity, and of the invasive ability and tube‐forming property of LECs by an MMP inhibitor. Furthermore, MMI270 was shown to strongly inhibit the activity of MMP‐2 and ‐9 produced by LLC cells and the invasion of these cells through Matrigel. In summary, the present results indicate that MMI270, apart from its anti‐tumor angio‐genic application, might be useful as an anti‐metastatic drug, on the basis of its downregulatation of both the lymphangiogenesis‐related properties of LECs and the invasive properties of LLC cells in vitro. (Cancer Sci 2004; 95: 25–31)</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/j.1349-7006.2004.tb03166.x</identifier><identifier>PMID: 14720323</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Angiogenesis ; Animal models ; Animals ; Biological and medical sciences ; Blotting, Western ; Carcinoma, Lewis Lung - drug therapy ; Carcinoma, Lewis Lung - secondary ; Cell adhesion & migration ; Cells, Cultured ; Endothelial cells ; Endothelial Cells - drug effects ; Enzymatic activity ; Female ; Intercellular adhesion molecule 1 ; Invasiveness ; Lung cancer ; Lymph nodes ; Lymphangiogenesis - drug effects ; Lymphatic Metastasis - pathology ; Matrix metalloproteinase ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases - drug effects ; Medical sciences ; Metalloproteinase ; Metastases ; Mice ; Neoplasm Invasiveness ; Pneumology ; Reverse Transcriptase Polymerase Chain Reaction ; Tissue Inhibitor of Metalloproteinases - pharmacology ; Tumors ; Tumors of the respiratory system and mediastinum ; Western blotting</subject><ispartof>Cancer science, 2004-01, Vol.95 (1), p.25-31</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright John Wiley & Sons, Inc. 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The observation that MMI270 led to a significant decrease in the weight of tumor‐metastasized lymph nodes of mice led us to test its anti‐lymphangiogenic and anti‐invasive effects in vitro. Murine LECs were characterized by an in vitro tube formation assay, by semi‐quantitative RT‐PCR assay to examine the expression of mRNAs for flt‐4, Flk‐1, Tie‐1, Tie‐2, CD54/ICAM1, vWF, MMPs and uPA, and by western blotting to confirm the protein expression of flt‐4 and CD31/PECAM. This is the first report on the expression of MMP‐2, MMP‐9 and MT1‐MMP in murine LECs, as well as on the inhibition of their enzymatic activity, and of the invasive ability and tube‐forming property of LECs by an MMP inhibitor. Furthermore, MMI270 was shown to strongly inhibit the activity of MMP‐2 and ‐9 produced by LLC cells and the invasion of these cells through Matrigel. In summary, the present results indicate that MMI270, apart from its anti‐tumor angio‐genic application, might be useful as an anti‐metastatic drug, on the basis of its downregulatation of both the lymphangiogenesis‐related properties of LECs and the invasive properties of LLC cells in vitro. (Cancer Sci 2004; 95: 25–31)</description><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Carcinoma, Lewis Lung - drug therapy</subject><subject>Carcinoma, Lewis Lung - secondary</subject><subject>Cell adhesion & migration</subject><subject>Cells, Cultured</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - drug effects</subject><subject>Enzymatic activity</subject><subject>Female</subject><subject>Intercellular adhesion molecule 1</subject><subject>Invasiveness</subject><subject>Lung cancer</subject><subject>Lymph nodes</subject><subject>Lymphangiogenesis - drug effects</subject><subject>Lymphatic Metastasis - pathology</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Matrix Metalloproteinases - drug effects</subject><subject>Medical sciences</subject><subject>Metalloproteinase</subject><subject>Metastases</subject><subject>Mice</subject><subject>Neoplasm Invasiveness</subject><subject>Pneumology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Tissue Inhibitor of Metalloproteinases - pharmacology</subject><subject>Tumors</subject><subject>Tumors of the respiratory system and mediastinum</subject><subject>Western blotting</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqVktuOFCEQhjtG466rr2CIRu96hD63iTGbiYdJduOFek04FDNMaBiB1pk7H8GH8Yl8EumZzq56JyGBUN9fVMGfZU8IXpA0XmwXpKz6vMW4WRQYV4vIcUmaZrG_k53fhO4e923e47I4yx6EsMW4bKq-up-dkaot0nF5nv1c2Y3mOmpnkVPIHIbdhtm1dmuwEHT49f2HB8MiSLTzbgc-aggTOYxeW5gFUQsEVrq4AaOZQQKMCYhZeYoj6ySgASILaeqj3ox2jQSzAjziB5SUaGDR6_2RM8al6yJoywIgfarReXR9vSpa_DC7p5gJ8GheL7LPb998Wr7Prz68Wy0vr3LR1FWdNx0IJYUihWg4aaWoFZOEq0LVWOCeA2EAlcQF5xVRHEvRQgeSi6pRoqvL8iJ7fcq7G_kAUoCNnhm683pg_kAd0_TviNUbunZfafqlusN9kzI8nzN492WEEOmgw_Q6zIIbA-0w7vumrxP49B9w60ZvU3e0KPu-LRLZJerliRLeheBB3dRC8HQpoVs6GYBOBqCTN-jsDbpP4sd_dnMrnc2QgGczwIJgRvn0OzrccnXdpaZI4l6duG_awOE_SqDLy49FXf4GMsbeqw</recordid><startdate>200401</startdate><enddate>200401</enddate><creator>Nakamura, Eliane Shizuka</creator><creator>Koizumi, Keiichi</creator><creator>Kobayashi, Mitsuo</creator><creator>Saiki, Ikuo</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><general>John Wiley & Sons, Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200401</creationdate><title>Inhibition of lymphangiogenesis‐related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270</title><author>Nakamura, Eliane Shizuka ; Koizumi, Keiichi ; Kobayashi, Mitsuo ; Saiki, Ikuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6545-68ecfdcf12c6b17dc5fad1bf2f50c09be1aee4d02bb41fb0dc7e8edbc46fc8533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Angiogenesis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Carcinoma, Lewis Lung - drug therapy</topic><topic>Carcinoma, Lewis Lung - secondary</topic><topic>Cell adhesion & migration</topic><topic>Cells, Cultured</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - drug effects</topic><topic>Enzymatic activity</topic><topic>Female</topic><topic>Intercellular adhesion molecule 1</topic><topic>Invasiveness</topic><topic>Lung cancer</topic><topic>Lymph nodes</topic><topic>Lymphangiogenesis - drug effects</topic><topic>Lymphatic Metastasis - pathology</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase Inhibitors</topic><topic>Matrix Metalloproteinases - drug effects</topic><topic>Medical sciences</topic><topic>Metalloproteinase</topic><topic>Metastases</topic><topic>Mice</topic><topic>Neoplasm Invasiveness</topic><topic>Pneumology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Tissue Inhibitor of Metalloproteinases - pharmacology</topic><topic>Tumors</topic><topic>Tumors of the respiratory system and mediastinum</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakamura, Eliane Shizuka</creatorcontrib><creatorcontrib>Koizumi, Keiichi</creatorcontrib><creatorcontrib>Kobayashi, Mitsuo</creatorcontrib><creatorcontrib>Saiki, Ikuo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Nakamura, Eliane Shizuka</au><au>Koizumi, Keiichi</au><au>Kobayashi, Mitsuo</au><au>Saiki, Ikuo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of lymphangiogenesis‐related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2004-01</date><risdate>2004</risdate><volume>95</volume><issue>1</issue><spage>25</spage><epage>31</epage><pages>25-31</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Based on a previous report on the effect of a matrix metalloproteinase (MMP) inhibitory compound, MMI270, in regulating tumor‐induced angiogenesis, as well as recent findings concerning functional correlations among tumor metastasis, angiogenesis and lymphangiogenesis, we investigated the anti‐metastatic efficacy of MMI270 in a murine model of lymph node metastasis of lung cancer, and analyzed whether this inhibitor could also regulate lymphangiogenesis‐related properties of murine lymphatic endothelial cells (LECs) and invasive properties of Lewis lung cancer (LLC) cells. The observation that MMI270 led to a significant decrease in the weight of tumor‐metastasized lymph nodes of mice led us to test its anti‐lymphangiogenic and anti‐invasive effects in vitro. Murine LECs were characterized by an in vitro tube formation assay, by semi‐quantitative RT‐PCR assay to examine the expression of mRNAs for flt‐4, Flk‐1, Tie‐1, Tie‐2, CD54/ICAM1, vWF, MMPs and uPA, and by western blotting to confirm the protein expression of flt‐4 and CD31/PECAM. This is the first report on the expression of MMP‐2, MMP‐9 and MT1‐MMP in murine LECs, as well as on the inhibition of their enzymatic activity, and of the invasive ability and tube‐forming property of LECs by an MMP inhibitor. Furthermore, MMI270 was shown to strongly inhibit the activity of MMP‐2 and ‐9 produced by LLC cells and the invasion of these cells through Matrigel. In summary, the present results indicate that MMI270, apart from its anti‐tumor angio‐genic application, might be useful as an anti‐metastatic drug, on the basis of its downregulatation of both the lymphangiogenesis‐related properties of LECs and the invasive properties of LLC cells in vitro. (Cancer Sci 2004; 95: 25–31)</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>14720323</pmid><doi>10.1111/j.1349-7006.2004.tb03166.x</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis Animal models Animals Biological and medical sciences Blotting, Western Carcinoma, Lewis Lung - drug therapy Carcinoma, Lewis Lung - secondary Cell adhesion & migration Cells, Cultured Endothelial cells Endothelial Cells - drug effects Enzymatic activity Female Intercellular adhesion molecule 1 Invasiveness Lung cancer Lymph nodes Lymphangiogenesis - drug effects Lymphatic Metastasis - pathology Matrix metalloproteinase Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases - drug effects Medical sciences Metalloproteinase Metastases Mice Neoplasm Invasiveness Pneumology Reverse Transcriptase Polymerase Chain Reaction Tissue Inhibitor of Metalloproteinases - pharmacology Tumors Tumors of the respiratory system and mediastinum Western blotting |
| title | Inhibition of lymphangiogenesis‐related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270 |
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