Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism
Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2004-07, Vol.64 (13), p.4481-4486 |
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| creator | FELDMAN, Andrew L STETLER-STEVENSON, William G O'CONNOR, Sarah LIBUTTI, Steven K COSTOUROS, Nick G KNEZEVIC, Vladimir BAIBAKOV, Galina ALEXANDER, H. Richard LORANG, Dominique HEWITT, Stephen M SEO, Dong-Wan MILLER, Marshall S |
| description | Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-03-2929 |
| format | Article |
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Richard ; LORANG, Dominique ; HEWITT, Stephen M ; SEO, Dong-Wan ; MILLER, Marshall S</creator><creatorcontrib>FELDMAN, Andrew L ; STETLER-STEVENSON, William G ; O'CONNOR, Sarah ; LIBUTTI, Steven K ; COSTOUROS, Nick G ; KNEZEVIC, Vladimir ; BAIBAKOV, Galina ; ALEXANDER, H. Richard ; LORANG, Dominique ; HEWITT, Stephen M ; SEO, Dong-Wan ; MILLER, Marshall S</creatorcontrib><description>Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-03-2929</identifier><identifier>PMID: 15231657</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Cycle Proteins ; Cell Division - physiology ; Colonic Neoplasms - blood supply ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Dual Specificity Phosphatase 1 ; Enzyme Induction ; Female ; Gene Expression Profiling ; Immediate-Early Proteins - biosynthesis ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases - metabolism ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - metabolism ; Neovascularization, Pathologic - pathology ; p38 Mitogen-Activated Protein Kinases ; Pharmacology. Drug treatments ; Phosphoprotein Phosphatases ; Phosphorylation ; Protein Phosphatase 1 ; Protein Tyrosine Phosphatases - biosynthesis ; Retroviridae - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Tissue Inhibitor of Metalloproteinase-2 - biosynthesis ; Tissue Inhibitor of Metalloproteinase-2 - genetics ; Tissue Inhibitor of Metalloproteinase-2 - physiology ; Transduction, Genetic ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2004-07, Vol.64 (13), p.4481-4486</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-5df5864f10a47b0456c79d8d20fdb8b04d88085329e894aaaabc8ee61c5c77633</citedby><cites>FETCH-LOGICAL-c369t-5df5864f10a47b0456c79d8d20fdb8b04d88085329e894aaaabc8ee61c5c77633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3357,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15918497$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15231657$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>FELDMAN, Andrew L</creatorcontrib><creatorcontrib>STETLER-STEVENSON, William G</creatorcontrib><creatorcontrib>O'CONNOR, Sarah</creatorcontrib><creatorcontrib>LIBUTTI, Steven K</creatorcontrib><creatorcontrib>COSTOUROS, Nick G</creatorcontrib><creatorcontrib>KNEZEVIC, Vladimir</creatorcontrib><creatorcontrib>BAIBAKOV, Galina</creatorcontrib><creatorcontrib>ALEXANDER, H. Richard</creatorcontrib><creatorcontrib>LORANG, Dominique</creatorcontrib><creatorcontrib>HEWITT, Stephen M</creatorcontrib><creatorcontrib>SEO, Dong-Wan</creatorcontrib><creatorcontrib>MILLER, Marshall S</creatorcontrib><title>Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Cycle Proteins</subject><subject>Cell Division - physiology</subject><subject>Colonic Neoplasms - blood supply</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Dual Specificity Phosphatase 1</subject><subject>Enzyme Induction</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Immediate-Early Proteins - biosynthesis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - metabolism</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphoprotein Phosphatases</subject><subject>Phosphorylation</subject><subject>Protein Phosphatase 1</subject><subject>Protein Tyrosine Phosphatases - biosynthesis</subject><subject>Retroviridae - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - biosynthesis</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - genetics</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - physiology</subject><subject>Transduction, Genetic</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkc1u1DAUha2qqB0Kj1DkTVmR1o5_s6xG_EkFNmVtOY4z4yqxi69T1BfguXGYEeCNdX2_c691DkKXlFxTKvQNIUQ3gqv2env7tSGsabu2O0EbKphuFOfiFG3-MufoJcBDLQUl4gydU9EyKoXaoF9f0rBMtoQUcRpxWeaUm32CgkMsPlu3duAdtnEX0s5HD-FPNRxQvMvpZ9nj_hmXALD4KtuHPpTaquNmX-w0pcecig_RgsctfgoWWxzTk59q3-1tDDC_Qi9GO4F_fbwv0PcP7--3n5q7bx8_b2_vGsdkVxoxjEJLPlJiueoJF9KpbtBDS8ah1_Vh0JpowdrO647benqnvZfUCaeUZOwCvT3MrV_6sXgoZg7g_DTZ6NMCRkqpOJGiguIAupwAsh_NYw6zzc-GErMGYFZzzWquqQEYwswaQNW9OS5Y-tkP_1RHxytwdQQsODuN2UYX4D-uo5p3iv0G1pORKg</recordid><startdate>20040701</startdate><enddate>20040701</enddate><creator>FELDMAN, Andrew L</creator><creator>STETLER-STEVENSON, William G</creator><creator>O'CONNOR, Sarah</creator><creator>LIBUTTI, Steven K</creator><creator>COSTOUROS, Nick G</creator><creator>KNEZEVIC, Vladimir</creator><creator>BAIBAKOV, Galina</creator><creator>ALEXANDER, H. 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Drug treatments</topic><topic>Phosphoprotein Phosphatases</topic><topic>Phosphorylation</topic><topic>Protein Phosphatase 1</topic><topic>Protein Tyrosine Phosphatases - biosynthesis</topic><topic>Retroviridae - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - biosynthesis</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - genetics</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - physiology</topic><topic>Transduction, Genetic</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>FELDMAN, Andrew L</creatorcontrib><creatorcontrib>STETLER-STEVENSON, William G</creatorcontrib><creatorcontrib>O'CONNOR, Sarah</creatorcontrib><creatorcontrib>LIBUTTI, Steven K</creatorcontrib><creatorcontrib>COSTOUROS, Nick G</creatorcontrib><creatorcontrib>KNEZEVIC, Vladimir</creatorcontrib><creatorcontrib>BAIBAKOV, Galina</creatorcontrib><creatorcontrib>ALEXANDER, H. 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Richard</au><au>LORANG, Dominique</au><au>HEWITT, Stephen M</au><au>SEO, Dong-Wan</au><au>MILLER, Marshall S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2004-07-01</date><risdate>2004</risdate><volume>64</volume><issue>13</issue><spage>4481</spage><epage>4486</epage><pages>4481-4486</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>15231657</pmid><doi>10.1158/0008-5472.CAN-03-2929</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2004-07, Vol.64 (13), p.4481-4486 |
| issn | 0008-5472 1538-7445 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic agents Biological and medical sciences Cell Cycle Proteins Cell Division - physiology Colonic Neoplasms - blood supply Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Dual Specificity Phosphatase 1 Enzyme Induction Female Gene Expression Profiling Immediate-Early Proteins - biosynthesis Medical sciences Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinases - metabolism Neovascularization, Pathologic - genetics Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology p38 Mitogen-Activated Protein Kinases Pharmacology. Drug treatments Phosphoprotein Phosphatases Phosphorylation Protein Phosphatase 1 Protein Tyrosine Phosphatases - biosynthesis Retroviridae - genetics Reverse Transcriptase Polymerase Chain Reaction Tissue Inhibitor of Metalloproteinase-2 - biosynthesis Tissue Inhibitor of Metalloproteinase-2 - genetics Tissue Inhibitor of Metalloproteinase-2 - physiology Transduction, Genetic Tumors |
| title | Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism |
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