TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer
Abstract Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC...
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| Veröffentlicht in: | Carcinogenesis (New York) 2020-05, Vol.41 (3), p.313-325 |
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| creator | Peeney, David Jensen, Sandra M Castro, Nadia P Kumar, Sarvesh Noonan, Silvia Handler, Chenchen Kuznetsov, Alex Shih, Joanna Tran, Andy D Salomon, David S Stetler-Stevenson, William G |
| description | Abstract
Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36–50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.
Exogenous TIMP-2 treatment inhibits TNBC growth and metastasis. The suppression of EMT and vascular normalization were observed in primary tumor tissues. Reduced stromal periostin localization and altered cell signaling pathways associated with metastasis formation are also detected. |
| doi_str_mv | 10.1093/carcin/bgz172 |
| format | Article |
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Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36–50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.
Exogenous TIMP-2 treatment inhibits TNBC growth and metastasis. The suppression of EMT and vascular normalization were observed in primary tumor tissues. Reduced stromal periostin localization and altered cell signaling pathways associated with metastasis formation are also detected.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgz172</identifier><identifier>PMID: 31621840</identifier><language>eng</language><publisher>UK: Oxford University Press</publisher><subject>Animals ; Carcinogenesis - genetics ; Cell Line, Tumor ; Cell Movement - genetics ; Cell Proliferation - genetics ; Disease Models, Animal ; Epithelial-Mesenchymal Transition - genetics ; Female ; Humans ; Inflammation, Microenvironment and Prevention ; Neoplasm Metastasis ; Phosphatidylinositol 3-Kinases ; Sequence Analysis, RNA ; Tissue Inhibitor of Metalloproteinase-2 - genetics ; Triple Negative Breast Neoplasms - genetics ; Triple Negative Breast Neoplasms - pathology ; Wnt Signaling Pathway - genetics ; Xenograft Model Antitumor Assays</subject><ispartof>Carcinogenesis (New York), 2020-05, Vol.41 (3), p.313-325</ispartof><rights>Published by Oxford University Press 2019. 2019</rights><rights>Published by Oxford University Press 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-195f46ada8f42fd89adfa0f69e89ed5fd6f60b378cd87b9ffd723695c3438a4f3</citedby><cites>FETCH-LOGICAL-c420t-195f46ada8f42fd89adfa0f69e89ed5fd6f60b378cd87b9ffd723695c3438a4f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31621840$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Peeney, David</creatorcontrib><creatorcontrib>Jensen, Sandra M</creatorcontrib><creatorcontrib>Castro, Nadia P</creatorcontrib><creatorcontrib>Kumar, Sarvesh</creatorcontrib><creatorcontrib>Noonan, Silvia</creatorcontrib><creatorcontrib>Handler, Chenchen</creatorcontrib><creatorcontrib>Kuznetsov, Alex</creatorcontrib><creatorcontrib>Shih, Joanna</creatorcontrib><creatorcontrib>Tran, Andy D</creatorcontrib><creatorcontrib>Salomon, David S</creatorcontrib><creatorcontrib>Stetler-Stevenson, William G</creatorcontrib><title>TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>Abstract
Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36–50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.
Exogenous TIMP-2 treatment inhibits TNBC growth and metastasis. The suppression of EMT and vascular normalization were observed in primary tumor tissues. Reduced stromal periostin localization and altered cell signaling pathways associated with metastasis formation are also detected.</description><subject>Animals</subject><subject>Carcinogenesis - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Cell Proliferation - genetics</subject><subject>Disease Models, Animal</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Inflammation, Microenvironment and Prevention</subject><subject>Neoplasm Metastasis</subject><subject>Phosphatidylinositol 3-Kinases</subject><subject>Sequence Analysis, RNA</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - genetics</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Wnt Signaling Pathway - genetics</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LwzAYgIMobk6PXiVHL3FJk6bNRZDhx2Cih3m1pPnoImtaknaiv95KVfQkBN5Dnvd54QHglOALggWdKxmU8_OyeidZsgemhHGMEpLjfTDFhFFEKWUTcBTjC8aE01QcggklfEAYnoLn9fL-ESUw9m0bTIwmwq6vmwCr0Lx2Gyi9hrXpZByei9B5WPfBeQPrRpstbCzsgmu3BnlTyc7tDCyDGWiopFcmHIMDK7fRnHzNGXi6uV4v7tDq4Xa5uFohxRLcISJSy7jUMrcssToXUluJLRcmF0anVnPLcUmzXOk8K4W1OksoF6mijOaSWToDl6O37cvaaGV8F-S2aIOrZXgrGumKvz_ebYqq2RVZkpAU80GARoEKTYzB2J9dgovP0MUYuhhDD_zZ74M_9HfZATgfgaZv_3F9AIQ0jLY</recordid><startdate>20200514</startdate><enddate>20200514</enddate><creator>Peeney, David</creator><creator>Jensen, Sandra M</creator><creator>Castro, Nadia P</creator><creator>Kumar, Sarvesh</creator><creator>Noonan, Silvia</creator><creator>Handler, Chenchen</creator><creator>Kuznetsov, Alex</creator><creator>Shih, Joanna</creator><creator>Tran, Andy D</creator><creator>Salomon, David S</creator><creator>Stetler-Stevenson, William G</creator><general>Oxford University Press</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>5PM</scope></search><sort><creationdate>20200514</creationdate><title>TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer</title><author>Peeney, David ; Jensen, Sandra M ; Castro, Nadia P ; Kumar, Sarvesh ; Noonan, Silvia ; Handler, Chenchen ; Kuznetsov, Alex ; Shih, Joanna ; Tran, Andy D ; Salomon, David S ; Stetler-Stevenson, William G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-195f46ada8f42fd89adfa0f69e89ed5fd6f60b378cd87b9ffd723695c3438a4f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Carcinogenesis - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Cell Proliferation - genetics</topic><topic>Disease Models, Animal</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Inflammation, Microenvironment and Prevention</topic><topic>Neoplasm Metastasis</topic><topic>Phosphatidylinositol 3-Kinases</topic><topic>Sequence Analysis, RNA</topic><topic>Tissue Inhibitor of Metalloproteinase-2 - genetics</topic><topic>Triple Negative Breast Neoplasms - genetics</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Wnt Signaling Pathway - genetics</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peeney, David</creatorcontrib><creatorcontrib>Jensen, Sandra M</creatorcontrib><creatorcontrib>Castro, Nadia P</creatorcontrib><creatorcontrib>Kumar, Sarvesh</creatorcontrib><creatorcontrib>Noonan, Silvia</creatorcontrib><creatorcontrib>Handler, Chenchen</creatorcontrib><creatorcontrib>Kuznetsov, Alex</creatorcontrib><creatorcontrib>Shih, Joanna</creatorcontrib><creatorcontrib>Tran, Andy D</creatorcontrib><creatorcontrib>Salomon, David S</creatorcontrib><creatorcontrib>Stetler-Stevenson, William G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peeney, David</au><au>Jensen, Sandra M</au><au>Castro, Nadia P</au><au>Kumar, Sarvesh</au><au>Noonan, Silvia</au><au>Handler, Chenchen</au><au>Kuznetsov, Alex</au><au>Shih, Joanna</au><au>Tran, Andy D</au><au>Salomon, David S</au><au>Stetler-Stevenson, William G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2020-05-14</date><risdate>2020</risdate><volume>41</volume><issue>3</issue><spage>313</spage><epage>325</epage><pages>313-325</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><abstract>Abstract
Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36–50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.
Exogenous TIMP-2 treatment inhibits TNBC growth and metastasis. The suppression of EMT and vascular normalization were observed in primary tumor tissues. Reduced stromal periostin localization and altered cell signaling pathways associated with metastasis formation are also detected.</abstract><cop>UK</cop><pub>Oxford University Press</pub><pmid>31621840</pmid><doi>10.1093/carcin/bgz172</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Carcinogenesis (New York), 2020-05, Vol.41 (3), p.313-325 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Animals Carcinogenesis - genetics Cell Line, Tumor Cell Movement - genetics Cell Proliferation - genetics Disease Models, Animal Epithelial-Mesenchymal Transition - genetics Female Humans Inflammation, Microenvironment and Prevention Neoplasm Metastasis Phosphatidylinositol 3-Kinases Sequence Analysis, RNA Tissue Inhibitor of Metalloproteinase-2 - genetics Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - pathology Wnt Signaling Pathway - genetics Xenograft Model Antitumor Assays |
| title | TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer |
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