Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy
Purpose: Midkine (MK) is a member of a family of heparin-binding growth factors, which was reported to have an important role in angiogenesis. Although MK was reported to be associated with bladder cancer progression, the functional significance of MK expression in bladder cancer progression has not...
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| Veröffentlicht in: | Clinical cancer research 2003-11, Vol.9 (14), p.5152-5160 |
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| creator | MURAMAKI, Mototsugu MIYAKE, Hideaki HARA, Isao KAMIDONO, Sadao |
| description | Purpose: Midkine (MK) is a member of a family of heparin-binding growth factors, which was reported to have an important role in angiogenesis.
Although MK was reported to be associated with bladder cancer progression, the functional significance of MK expression in
bladder cancer progression has not been elucidated. The objectives of this study were to determine whether overexpression
of MK in bladder cancer cells enhances their malignant potential and to evaluate the inhibitory effect of the antiangiogenic
agent TNP-470 on the growth of MK-overexpressing bladder cancer cells in vivo .
Experimental Design: We introduced the MK gene into human bladder cancer UM-UC-3 cells that do not secrete a detectable level of MK protein and generated the MK-overexpressing
cell line UM-UC-3/MK. The biological activity of secreted MK was evaluated using a human umbilical vein endothelial cell proliferation
assay. To investigate the in vivo effects of MK overexpression on tumor growth, each cell line was injected s.c. and orthotopically into nude mice. To evaluate
the therapeutic effects of the antiangiogenic agent, mice were given TNP-470 after s.c. injection of each cell line. The microvessel
density of tumors was quantitated by immunohistochemistry of CD31.
Results: The heparin affinity-purified conditioned media of UM-UC-3/MK cells significantly enhanced human umbilical vein endothelial
cell proliferation. MK expression had no effect on in vitro growth but conferred a growth advantage on both s.c. and orthotopic tumors in vivo . Furthermore, enhanced tumor growth was closely associated with increased microvessel density. Significant inhibition of
tumor growth by TNP-470 treatment was observed only in UM-UC-3/MK tumors and not in control tumors.
Conclusions: We demonstrated that overexpression of the MK gene causes an increase in the angiogenic activity of cells through vascular endothelial cell growth, resulting in enhanced
malignant potential of human bladder cancer cells. Moreover, the present findings suggest that TNP-470 could be used as a
novel therapeutic adjunct to conventional agents for patients with advanced bladder cancer overexpressing MK. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_71368146</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>71368146</sourcerecordid><originalsourceid>FETCH-LOGICAL-h270t-cd09229c997940ebbf1e6d7c4cadf6cecbcfa71a24656b22aa45e98581b0408d3</originalsourceid><addsrcrecordid>eNpF0M1O3DAQB_AItQIKvALyhaqXSLbjfPgIKz5WArVS6Tma2JPNQNZZbAe0j9K3rbds6cXjkX6asf8H2bEoyzovZFV-SndeNzlXhTzKvoTwxLlQgqvD7EioShRaq-Ps99JFP9nZRJocm3r2QPaZHLJbTAe5OLG7eQ2OXY1gLXq2AGd2BccxsGs37NrAHgckzx5gpJUDF9mPAd0UtxtkV3NkS2c8QvhwP9EFivRKccvSgksXCdyKphU6MjvjYbM9zT73MAY829eT7NfN9ePiLr__frtcXN7ng6x5zI3lWkpttK614th1vcDK1kYZsH1l0HSmh1qAVFVZdVICqBJ1Uzai44o3tjjJvr7P3fjpZcYQ2zUFk74HDqc5tLUoqiYFluD5Hs7dGm278bQGv23_hZnAxR5AMDD2PmVD4b8rZXppI5P79u4GWg1v5LE1f0P1GBC8GVqdZrZl8sUfrrqPZA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>71368146</pqid></control><display><type>article</type><title>Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>MURAMAKI, Mototsugu ; MIYAKE, Hideaki ; HARA, Isao ; KAMIDONO, Sadao</creator><creatorcontrib>MURAMAKI, Mototsugu ; MIYAKE, Hideaki ; HARA, Isao ; KAMIDONO, Sadao</creatorcontrib><description>Purpose: Midkine (MK) is a member of a family of heparin-binding growth factors, which was reported to have an important role in angiogenesis.
Although MK was reported to be associated with bladder cancer progression, the functional significance of MK expression in
bladder cancer progression has not been elucidated. The objectives of this study were to determine whether overexpression
of MK in bladder cancer cells enhances their malignant potential and to evaluate the inhibitory effect of the antiangiogenic
agent TNP-470 on the growth of MK-overexpressing bladder cancer cells in vivo .
Experimental Design: We introduced the MK gene into human bladder cancer UM-UC-3 cells that do not secrete a detectable level of MK protein and generated the MK-overexpressing
cell line UM-UC-3/MK. The biological activity of secreted MK was evaluated using a human umbilical vein endothelial cell proliferation
assay. To investigate the in vivo effects of MK overexpression on tumor growth, each cell line was injected s.c. and orthotopically into nude mice. To evaluate
the therapeutic effects of the antiangiogenic agent, mice were given TNP-470 after s.c. injection of each cell line. The microvessel
density of tumors was quantitated by immunohistochemistry of CD31.
Results: The heparin affinity-purified conditioned media of UM-UC-3/MK cells significantly enhanced human umbilical vein endothelial
cell proliferation. MK expression had no effect on in vitro growth but conferred a growth advantage on both s.c. and orthotopic tumors in vivo . Furthermore, enhanced tumor growth was closely associated with increased microvessel density. Significant inhibition of
tumor growth by TNP-470 treatment was observed only in UM-UC-3/MK tumors and not in control tumors.
Conclusions: We demonstrated that overexpression of the MK gene causes an increase in the angiogenic activity of cells through vascular endothelial cell growth, resulting in enhanced
malignant potential of human bladder cancer cells. Moreover, the present findings suggest that TNP-470 could be used as a
novel therapeutic adjunct to conventional agents for patients with advanced bladder cancer overexpressing MK.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 14613994</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Angiogenesis Inhibitors - therapeutic use ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Division - drug effects ; Cell Movement ; Cell Transformation, Neoplastic ; Cyclohexanes ; Cytokines ; Disease Progression ; Dissemination ; Drug Resistance, Neoplasm ; Endothelium, Vascular - cytology ; Gene Expression Regulation, Neoplastic - physiology ; General aspects ; Humans ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Invasiveness ; Neovascularization, Pathologic - drug therapy ; Pharmacology. Drug treatments ; Phenotype ; Sesquiterpenes - therapeutic use ; Transfection ; Tumor cell ; Tumor Cells, Cultured ; Tumors ; Umbilical Veins ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - metabolism</subject><ispartof>Clinical cancer research, 2003-11, Vol.9 (14), p.5152-5160</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15292282$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14613994$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MURAMAKI, Mototsugu</creatorcontrib><creatorcontrib>MIYAKE, Hideaki</creatorcontrib><creatorcontrib>HARA, Isao</creatorcontrib><creatorcontrib>KAMIDONO, Sadao</creatorcontrib><title>Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: Midkine (MK) is a member of a family of heparin-binding growth factors, which was reported to have an important role in angiogenesis.
Although MK was reported to be associated with bladder cancer progression, the functional significance of MK expression in
bladder cancer progression has not been elucidated. The objectives of this study were to determine whether overexpression
of MK in bladder cancer cells enhances their malignant potential and to evaluate the inhibitory effect of the antiangiogenic
agent TNP-470 on the growth of MK-overexpressing bladder cancer cells in vivo .
Experimental Design: We introduced the MK gene into human bladder cancer UM-UC-3 cells that do not secrete a detectable level of MK protein and generated the MK-overexpressing
cell line UM-UC-3/MK. The biological activity of secreted MK was evaluated using a human umbilical vein endothelial cell proliferation
assay. To investigate the in vivo effects of MK overexpression on tumor growth, each cell line was injected s.c. and orthotopically into nude mice. To evaluate
the therapeutic effects of the antiangiogenic agent, mice were given TNP-470 after s.c. injection of each cell line. The microvessel
density of tumors was quantitated by immunohistochemistry of CD31.
Results: The heparin affinity-purified conditioned media of UM-UC-3/MK cells significantly enhanced human umbilical vein endothelial
cell proliferation. MK expression had no effect on in vitro growth but conferred a growth advantage on both s.c. and orthotopic tumors in vivo . Furthermore, enhanced tumor growth was closely associated with increased microvessel density. Significant inhibition of
tumor growth by TNP-470 treatment was observed only in UM-UC-3/MK tumors and not in control tumors.
Conclusions: We demonstrated that overexpression of the MK gene causes an increase in the angiogenic activity of cells through vascular endothelial cell growth, resulting in enhanced
malignant potential of human bladder cancer cells. Moreover, the present findings suggest that TNP-470 could be used as a
novel therapeutic adjunct to conventional agents for patients with advanced bladder cancer overexpressing MK.</description><subject>Angiogenesis Inhibitors - therapeutic use</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Division - drug effects</subject><subject>Cell Movement</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cyclohexanes</subject><subject>Cytokines</subject><subject>Disease Progression</subject><subject>Dissemination</subject><subject>Drug Resistance, Neoplasm</subject><subject>Endothelium, Vascular - cytology</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Neoplasm Invasiveness</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Sesquiterpenes - therapeutic use</subject><subject>Transfection</subject><subject>Tumor cell</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Umbilical Veins</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><subject>Urinary Bladder Neoplasms - metabolism</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0M1O3DAQB_AItQIKvALyhaqXSLbjfPgIKz5WArVS6Tma2JPNQNZZbAe0j9K3rbds6cXjkX6asf8H2bEoyzovZFV-SndeNzlXhTzKvoTwxLlQgqvD7EioShRaq-Ps99JFP9nZRJocm3r2QPaZHLJbTAe5OLG7eQ2OXY1gLXq2AGd2BccxsGs37NrAHgckzx5gpJUDF9mPAd0UtxtkV3NkS2c8QvhwP9EFivRKccvSgksXCdyKphU6MjvjYbM9zT73MAY829eT7NfN9ePiLr__frtcXN7ng6x5zI3lWkpttK614th1vcDK1kYZsH1l0HSmh1qAVFVZdVICqBJ1Uzai44o3tjjJvr7P3fjpZcYQ2zUFk74HDqc5tLUoqiYFluD5Hs7dGm278bQGv23_hZnAxR5AMDD2PmVD4b8rZXppI5P79u4GWg1v5LE1f0P1GBC8GVqdZrZl8sUfrrqPZA</recordid><startdate>20031101</startdate><enddate>20031101</enddate><creator>MURAMAKI, Mototsugu</creator><creator>MIYAKE, Hideaki</creator><creator>HARA, Isao</creator><creator>KAMIDONO, Sadao</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>7X8</scope></search><sort><creationdate>20031101</creationdate><title>Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy</title><author>MURAMAKI, Mototsugu ; MIYAKE, Hideaki ; HARA, Isao ; KAMIDONO, Sadao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h270t-cd09229c997940ebbf1e6d7c4cadf6cecbcfa71a24656b22aa45e98581b0408d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Angiogenesis Inhibitors - therapeutic use</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Division - drug effects</topic><topic>Cell Movement</topic><topic>Cell Transformation, Neoplastic</topic><topic>Cyclohexanes</topic><topic>Cytokines</topic><topic>Disease Progression</topic><topic>Dissemination</topic><topic>Drug Resistance, Neoplasm</topic><topic>Endothelium, Vascular - cytology</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>General aspects</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Neoplasm Invasiveness</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenotype</topic><topic>Sesquiterpenes - therapeutic use</topic><topic>Transfection</topic><topic>Tumor cell</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><topic>Umbilical Veins</topic><topic>Urinary Bladder Neoplasms - drug therapy</topic><topic>Urinary Bladder Neoplasms - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MURAMAKI, Mototsugu</creatorcontrib><creatorcontrib>MIYAKE, Hideaki</creatorcontrib><creatorcontrib>HARA, Isao</creatorcontrib><creatorcontrib>KAMIDONO, Sadao</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>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MURAMAKI, Mototsugu</au><au>MIYAKE, Hideaki</au><au>HARA, Isao</au><au>KAMIDONO, Sadao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2003-11-01</date><risdate>2003</risdate><volume>9</volume><issue>14</issue><spage>5152</spage><epage>5160</epage><pages>5152-5160</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: Midkine (MK) is a member of a family of heparin-binding growth factors, which was reported to have an important role in angiogenesis.
Although MK was reported to be associated with bladder cancer progression, the functional significance of MK expression in
bladder cancer progression has not been elucidated. The objectives of this study were to determine whether overexpression
of MK in bladder cancer cells enhances their malignant potential and to evaluate the inhibitory effect of the antiangiogenic
agent TNP-470 on the growth of MK-overexpressing bladder cancer cells in vivo .
Experimental Design: We introduced the MK gene into human bladder cancer UM-UC-3 cells that do not secrete a detectable level of MK protein and generated the MK-overexpressing
cell line UM-UC-3/MK. The biological activity of secreted MK was evaluated using a human umbilical vein endothelial cell proliferation
assay. To investigate the in vivo effects of MK overexpression on tumor growth, each cell line was injected s.c. and orthotopically into nude mice. To evaluate
the therapeutic effects of the antiangiogenic agent, mice were given TNP-470 after s.c. injection of each cell line. The microvessel
density of tumors was quantitated by immunohistochemistry of CD31.
Results: The heparin affinity-purified conditioned media of UM-UC-3/MK cells significantly enhanced human umbilical vein endothelial
cell proliferation. MK expression had no effect on in vitro growth but conferred a growth advantage on both s.c. and orthotopic tumors in vivo . Furthermore, enhanced tumor growth was closely associated with increased microvessel density. Significant inhibition of
tumor growth by TNP-470 treatment was observed only in UM-UC-3/MK tumors and not in control tumors.
Conclusions: We demonstrated that overexpression of the MK gene causes an increase in the angiogenic activity of cells through vascular endothelial cell growth, resulting in enhanced
malignant potential of human bladder cancer cells. Moreover, the present findings suggest that TNP-470 could be used as a
novel therapeutic adjunct to conventional agents for patients with advanced bladder cancer overexpressing MK.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>14613994</pmid><tpages>9</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Angiogenesis Inhibitors - therapeutic use Animals Antineoplastic agents Biological and medical sciences Carrier Proteins - genetics Carrier Proteins - metabolism Cell Division - drug effects Cell Movement Cell Transformation, Neoplastic Cyclohexanes Cytokines Disease Progression Dissemination Drug Resistance, Neoplasm Endothelium, Vascular - cytology Gene Expression Regulation, Neoplastic - physiology General aspects Humans Medical sciences Mice Mice, Inbred BALB C Mice, Nude Neoplasm Invasiveness Neovascularization, Pathologic - drug therapy Pharmacology. Drug treatments Phenotype Sesquiterpenes - therapeutic use Transfection Tumor cell Tumor Cells, Cultured Tumors Umbilical Veins Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - metabolism |
| title | Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy |
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