CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (...
Gespeichert in:
Veröffentlicht in: | Molecular biology of the cell 2014-03, Vol.25 (5), p.566-582 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 582 |
---|---|
container_issue | 5 |
container_start_page | 566 |
container_title | Molecular biology of the cell |
container_volume | 25 |
creator | Sobolik, Tammy Su, Ying-Jun Wells, Sam Ayers, Gregory D Cook, Rebecca S Richmond, Ann |
description | Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis. |
doi_str_mv | 10.1091/mbc.e13-07-0360 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3937084</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1503549772</sourcerecordid><originalsourceid>FETCH-LOGICAL-c505t-1119522b260f5419ee413003e1ca4edfe18d9b62bca5f1c1941f30a152234c883</originalsourceid><addsrcrecordid>eNpVkUtP3DAURq2KqlDKmh3ykk3A148k3iBVIygIqlZVK7GzHOeGBE3i1Hammn-PpzzUrmx99_izrUPIMbAzYBrOx8adIYiCVQUTJXtHDkALXUhVl3t5z5QuQHG5Tz7G-MgYSFlWH8g-l3KH8wOyXd2vfkjahmGDkaYe6YjJxmTT4Ojc4-TTdkY6TLQJmHPq7OQwZDL45aHPg3ZxafAT9R3ddXFqp5banG3sa_718vZv-v1G3NLZpv6P3cZP5H1n1xGPXtZD8uvq8ufqurj79uVm9fmucIqpVACAVpw3vGSdkqARJQjGBIKzEtsOoW51U_LGWdWBAy2hE8zmX3MhXV2LQ3Lx3DsvzYitwykFuzZzGEYbtsbbwfw_mYbePPiNEVpUrJa54PSlIPjfC8ZkxiE6XK_thH6JBhQTSuqq4hk9f0Zd8DEG7N6uAWZ2wkwWZrIwwyqzM5BPnPz7ujf-1ZB4AtiGkkQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1503549772</pqid></control><display><type>article</type><title>CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways</title><source>MEDLINE</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Sobolik, Tammy ; Su, Ying-Jun ; Wells, Sam ; Ayers, Gregory D ; Cook, Rebecca S ; Richmond, Ann</creator><contributor>Yap, Alpha</contributor><creatorcontrib>Sobolik, Tammy ; Su, Ying-Jun ; Wells, Sam ; Ayers, Gregory D ; Cook, Rebecca S ; Richmond, Ann ; Yap, Alpha</creatorcontrib><description>Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.</description><identifier>ISSN: 1059-1524</identifier><identifier>EISSN: 1939-4586</identifier><identifier>DOI: 10.1091/mbc.e13-07-0360</identifier><identifier>PMID: 24403602</identifier><language>eng</language><publisher>United States: The American Society for Cell Biology</publisher><subject>Animals ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Movement - genetics ; Epithelial-Mesenchymal Transition - genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Association Studies ; HEK293 Cells ; HL-60 Cells ; Humans ; Lymph Nodes - pathology ; MAP Kinase Signaling System ; MCF-7 Cells ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Models, Biological ; Neoplasm Invasiveness - genetics ; Neoplasm Invasiveness - pathology ; Neoplasm Metastasis - genetics ; Neoplasm Metastasis - pathology ; Phosphatidylinositol Phosphates - metabolism ; Receptors, CXCR4 - genetics ; Receptors, CXCR4 - metabolism ; Receptors, Interleukin-8B - genetics ; Receptors, Interleukin-8B - metabolism ; Signal Transduction - genetics ; Up-Regulation</subject><ispartof>Molecular biology of the cell, 2014-03, Vol.25 (5), p.566-582</ispartof><rights>2014 Sobolik This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( ). 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c505t-1119522b260f5419ee413003e1ca4edfe18d9b62bca5f1c1941f30a152234c883</citedby><cites>FETCH-LOGICAL-c505t-1119522b260f5419ee413003e1ca4edfe18d9b62bca5f1c1941f30a152234c883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937084/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937084/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24403602$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yap, Alpha</contributor><creatorcontrib>Sobolik, Tammy</creatorcontrib><creatorcontrib>Su, Ying-Jun</creatorcontrib><creatorcontrib>Wells, Sam</creatorcontrib><creatorcontrib>Ayers, Gregory D</creatorcontrib><creatorcontrib>Cook, Rebecca S</creatorcontrib><creatorcontrib>Richmond, Ann</creatorcontrib><title>CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways</title><title>Molecular biology of the cell</title><addtitle>Mol Biol Cell</addtitle><description>Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.</description><subject>Animals</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic Association Studies</subject><subject>HEK293 Cells</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Lymph Nodes - pathology</subject><subject>MAP Kinase Signaling System</subject><subject>MCF-7 Cells</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Models, Biological</subject><subject>Neoplasm Invasiveness - genetics</subject><subject>Neoplasm Invasiveness - pathology</subject><subject>Neoplasm Metastasis - genetics</subject><subject>Neoplasm Metastasis - pathology</subject><subject>Phosphatidylinositol Phosphates - metabolism</subject><subject>Receptors, CXCR4 - genetics</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Receptors, Interleukin-8B - genetics</subject><subject>Receptors, Interleukin-8B - metabolism</subject><subject>Signal Transduction - genetics</subject><subject>Up-Regulation</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtP3DAURq2KqlDKmh3ykk3A148k3iBVIygIqlZVK7GzHOeGBE3i1Hammn-PpzzUrmx99_izrUPIMbAzYBrOx8adIYiCVQUTJXtHDkALXUhVl3t5z5QuQHG5Tz7G-MgYSFlWH8g-l3KH8wOyXd2vfkjahmGDkaYe6YjJxmTT4Ojc4-TTdkY6TLQJmHPq7OQwZDL45aHPg3ZxafAT9R3ddXFqp5banG3sa_718vZv-v1G3NLZpv6P3cZP5H1n1xGPXtZD8uvq8ufqurj79uVm9fmucIqpVACAVpw3vGSdkqARJQjGBIKzEtsOoW51U_LGWdWBAy2hE8zmX3MhXV2LQ3Lx3DsvzYitwykFuzZzGEYbtsbbwfw_mYbePPiNEVpUrJa54PSlIPjfC8ZkxiE6XK_thH6JBhQTSuqq4hk9f0Zd8DEG7N6uAWZ2wkwWZrIwwyqzM5BPnPz7ujf-1ZB4AtiGkkQ</recordid><startdate>201403</startdate><enddate>201403</enddate><creator>Sobolik, Tammy</creator><creator>Su, Ying-Jun</creator><creator>Wells, Sam</creator><creator>Ayers, Gregory D</creator><creator>Cook, Rebecca S</creator><creator>Richmond, Ann</creator><general>The American Society for Cell Biology</general><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><scope>5PM</scope></search><sort><creationdate>201403</creationdate><title>CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways</title><author>Sobolik, Tammy ; Su, Ying-Jun ; Wells, Sam ; Ayers, Gregory D ; Cook, Rebecca S ; Richmond, Ann</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c505t-1119522b260f5419ee413003e1ca4edfe18d9b62bca5f1c1941f30a152234c883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic Association Studies</topic><topic>HEK293 Cells</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Lymph Nodes - pathology</topic><topic>MAP Kinase Signaling System</topic><topic>MCF-7 Cells</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Models, Biological</topic><topic>Neoplasm Invasiveness - genetics</topic><topic>Neoplasm Invasiveness - pathology</topic><topic>Neoplasm Metastasis - genetics</topic><topic>Neoplasm Metastasis - pathology</topic><topic>Phosphatidylinositol Phosphates - metabolism</topic><topic>Receptors, CXCR4 - genetics</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Receptors, Interleukin-8B - genetics</topic><topic>Receptors, Interleukin-8B - metabolism</topic><topic>Signal Transduction - genetics</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sobolik, Tammy</creatorcontrib><creatorcontrib>Su, Ying-Jun</creatorcontrib><creatorcontrib>Wells, Sam</creatorcontrib><creatorcontrib>Ayers, Gregory D</creatorcontrib><creatorcontrib>Cook, Rebecca S</creatorcontrib><creatorcontrib>Richmond, Ann</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sobolik, Tammy</au><au>Su, Ying-Jun</au><au>Wells, Sam</au><au>Ayers, Gregory D</au><au>Cook, Rebecca S</au><au>Richmond, Ann</au><au>Yap, Alpha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2014-03</date><risdate>2014</risdate><volume>25</volume><issue>5</issue><spage>566</spage><epage>582</epage><pages>566-582</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.</abstract><cop>United States</cop><pub>The American Society for Cell Biology</pub><pmid>24403602</pmid><doi>10.1091/mbc.e13-07-0360</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1059-1524 |
ispartof | Molecular biology of the cell, 2014-03, Vol.25 (5), p.566-582 |
issn | 1059-1524 1939-4586 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3937084 |
source | MEDLINE; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Animals Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Cell Movement - genetics Epithelial-Mesenchymal Transition - genetics Female Gene Expression Regulation, Neoplastic Genetic Association Studies HEK293 Cells HL-60 Cells Humans Lymph Nodes - pathology MAP Kinase Signaling System MCF-7 Cells Mice Mice, Inbred BALB C Mice, Nude Models, Biological Neoplasm Invasiveness - genetics Neoplasm Invasiveness - pathology Neoplasm Metastasis - genetics Neoplasm Metastasis - pathology Phosphatidylinositol Phosphates - metabolism Receptors, CXCR4 - genetics Receptors, CXCR4 - metabolism Receptors, Interleukin-8B - genetics Receptors, Interleukin-8B - metabolism Signal Transduction - genetics Up-Regulation |
title | CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T22%3A57%3A25IST&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=CXCR4%20drives%20the%20metastatic%20phenotype%20in%20breast%20cancer%20through%20induction%20of%20CXCR2%20and%20activation%20of%20MEK%20and%20PI3K%20pathways&rft.jtitle=Molecular%20biology%20of%20the%20cell&rft.au=Sobolik,%20Tammy&rft.date=2014-03&rft.volume=25&rft.issue=5&rft.spage=566&rft.epage=582&rft.pages=566-582&rft.issn=1059-1524&rft.eissn=1939-4586&rft_id=info:doi/10.1091/mbc.e13-07-0360&rft_dat=%3Cproquest_pubme%3E1503549772%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=1503549772&rft_id=info:pmid/24403602&rfr_iscdi=true |