Matrix Metalloproteinase-14 (MTi-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis
Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-05, Vol.70 (10), p.4141-4150 |
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| creator | HAWINKELS, Lukas J. A. C KUIPER, Patricia WIERCINSKA, Eliza VERSPAGET, Hein W ZHEN LIU PARDALI, Evangelia SIE, Cornelis F. M TEN DIJKE, Peter |
| description | Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment. |
| doi_str_mv | 10.1158/0008-5472.can-09-4466 |
| format | Article |
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A. C ; KUIPER, Patricia ; WIERCINSKA, Eliza ; VERSPAGET, Hein W ; ZHEN LIU ; PARDALI, Evangelia ; SIE, Cornelis F. M ; TEN DIJKE, Peter</creator><creatorcontrib>HAWINKELS, Lukas J. A. C ; KUIPER, Patricia ; WIERCINSKA, Eliza ; VERSPAGET, Hein W ; ZHEN LIU ; PARDALI, Evangelia ; SIE, Cornelis F. M ; TEN DIJKE, Peter</creatorcontrib><description>Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-09-4466</identifier><identifier>PMID: 20424116</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenoma - blood supply ; Adenoma - metabolism ; Adenoma - prevention & control ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antineoplastic agents ; Biological and medical sciences ; Cell Membrane - metabolism ; Cells, Cultured ; Cercopithecus aethiops ; Colon - cytology ; Colon - metabolism ; Colorectal Neoplasms - blood supply ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - prevention & control ; COS Cells ; Endoglin ; Endothelium, Vascular - cytology ; Endothelium, Vascular - metabolism ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoenzyme Techniques ; Matrix Metalloproteinase 14 - genetics ; Matrix Metalloproteinase 14 - metabolism ; Matrix Metalloproteinase Inhibitors ; Medical sciences ; Neovascularization, Pathologic - prevention & control ; Pharmacology. Drug treatments ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Rectum - cytology ; Rectum - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Small Interfering - pharmacology ; Tumors ; Umbilical Veins - cytology ; Umbilical Veins - metabolism</subject><ispartof>Cancer research (Chicago, Ill.), 2010-05, Vol.70 (10), p.4141-4150</ispartof><rights>2015 INIST-CNRS</rights><rights>(c)2010 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-46733564a56295be16a3125d5613ff1566a3b5f1763bc2eb13ec7bb79d50468c3</citedby><cites>FETCH-LOGICAL-c451t-46733564a56295be16a3125d5613ff1566a3b5f1763bc2eb13ec7bb79d50468c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22774149$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20424116$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HAWINKELS, Lukas J. A. C</creatorcontrib><creatorcontrib>KUIPER, Patricia</creatorcontrib><creatorcontrib>WIERCINSKA, Eliza</creatorcontrib><creatorcontrib>VERSPAGET, Hein W</creatorcontrib><creatorcontrib>ZHEN LIU</creatorcontrib><creatorcontrib>PARDALI, Evangelia</creatorcontrib><creatorcontrib>SIE, Cornelis F. M</creatorcontrib><creatorcontrib>TEN DIJKE, Peter</creatorcontrib><title>Matrix Metalloproteinase-14 (MTi-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment.</description><subject>Adenoma - blood supply</subject><subject>Adenoma - metabolism</subject><subject>Adenoma - prevention & control</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Membrane - metabolism</subject><subject>Cells, Cultured</subject><subject>Cercopithecus aethiops</subject><subject>Colon - cytology</subject><subject>Colon - metabolism</subject><subject>Colorectal Neoplasms - blood supply</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - prevention & control</subject><subject>COS Cells</subject><subject>Endoglin</subject><subject>Endothelium, Vascular - cytology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Matrix Metalloproteinase 14 - genetics</subject><subject>Matrix Metalloproteinase 14 - metabolism</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Medical sciences</subject><subject>Neovascularization, Pathologic - prevention & control</subject><subject>Pharmacology. Drug treatments</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Rectum - cytology</subject><subject>Rectum - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>Tumors</subject><subject>Umbilical Veins - cytology</subject><subject>Umbilical Veins - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1Lw0AQhhdRtFZ_gpKLqIfVnexHkmMpVQtGBetNWDabSbuSbmo2Bf33prTqaRh43neGh5AzYDcAMr1ljKVUiiS-scZTllEhlNojA5A8pYkQcp8M_pgjchzCR79KYPKQHMVMxAJADch7brrWfUU5dqaum1XbdOi8CUhBRFf5zNE8f7mmOZbOdFhGE18289r56HWBZen8PJr6hStcF6LZetm00cjPXTNHj8GFE3JQmTrg6W4OydvdZDZ-oI_P99Px6JFaIaGjQiWcSyWMVHEmCwRlOMSylAp4VYFU_V7IChLFCxtjARxtUhRJVkomVGr5kFxue_v3P9cYOr10wWJdG4_NOui-njNIY9WTckvatgmhxUqvWrc07bcGpjde9caZ3jjT49GTZpneeO1z57sL62KJ5V_qV2QPXOwAE6ypq9Z468I_FyeJAJHxH2pYf0A</recordid><startdate>20100515</startdate><enddate>20100515</enddate><creator>HAWINKELS, Lukas J. A. C</creator><creator>KUIPER, Patricia</creator><creator>WIERCINSKA, Eliza</creator><creator>VERSPAGET, Hein W</creator><creator>ZHEN LIU</creator><creator>PARDALI, Evangelia</creator><creator>SIE, Cornelis F. M</creator><creator>TEN DIJKE, Peter</creator><general>American Association for Cancer Research</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>7X8</scope></search><sort><creationdate>20100515</creationdate><title>Matrix Metalloproteinase-14 (MTi-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis</title><author>HAWINKELS, Lukas J. A. C ; KUIPER, Patricia ; WIERCINSKA, Eliza ; VERSPAGET, Hein W ; ZHEN LIU ; PARDALI, Evangelia ; SIE, Cornelis F. 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Drug treatments</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Rectum - cytology</topic><topic>Rectum - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>Tumors</topic><topic>Umbilical Veins - cytology</topic><topic>Umbilical Veins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HAWINKELS, Lukas J. A. C</creatorcontrib><creatorcontrib>KUIPER, Patricia</creatorcontrib><creatorcontrib>WIERCINSKA, Eliza</creatorcontrib><creatorcontrib>VERSPAGET, Hein W</creatorcontrib><creatorcontrib>ZHEN LIU</creatorcontrib><creatorcontrib>PARDALI, Evangelia</creatorcontrib><creatorcontrib>SIE, Cornelis F. M</creatorcontrib><creatorcontrib>TEN DIJKE, Peter</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>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HAWINKELS, Lukas J. A. C</au><au>KUIPER, Patricia</au><au>WIERCINSKA, Eliza</au><au>VERSPAGET, Hein W</au><au>ZHEN LIU</au><au>PARDALI, Evangelia</au><au>SIE, Cornelis F. M</au><au>TEN DIJKE, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Matrix Metalloproteinase-14 (MTi-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2010-05-15</date><risdate>2010</risdate><volume>70</volume><issue>10</issue><spage>4141</spage><epage>4150</epage><pages>4141-4150</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>20424116</pmid><doi>10.1158/0008-5472.can-09-4466</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoma - blood supply Adenoma - metabolism Adenoma - prevention & control Animals Antigens, CD - genetics Antigens, CD - metabolism Antineoplastic agents Biological and medical sciences Cell Membrane - metabolism Cells, Cultured Cercopithecus aethiops Colon - cytology Colon - metabolism Colorectal Neoplasms - blood supply Colorectal Neoplasms - metabolism Colorectal Neoplasms - prevention & control COS Cells Endoglin Endothelium, Vascular - cytology Endothelium, Vascular - metabolism Enzyme-Linked Immunosorbent Assay Humans Immunoenzyme Techniques Matrix Metalloproteinase 14 - genetics Matrix Metalloproteinase 14 - metabolism Matrix Metalloproteinase Inhibitors Medical sciences Neovascularization, Pathologic - prevention & control Pharmacology. Drug treatments Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Rectum - cytology Rectum - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Messenger - metabolism RNA, Small Interfering - pharmacology Tumors Umbilical Veins - cytology Umbilical Veins - metabolism |
| title | Matrix Metalloproteinase-14 (MTi-MMP)-Mediated Endoglin Shedding Inhibits Tumor Angiogenesis |
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