Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fib...
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Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
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Kojima, Yasushi Acar, Ahmet Eaton, Elinor Ng Mellody, Kieran T Scheel, Christina Ben-Porath, Ittai Onder, Tamer T Wang, Zhigang C Richardson, Andrea L Weinberg, Robert A Orimo, Akira |
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Animals Autocrine Communication Biological Sciences Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Breasts Cancer Carcinoma Cell Differentiation Chemokine CXCL12 - metabolism Epithelial cells Female Fibroblasts Humans Mammary Glands, Human - metabolism Mammary Glands, Human - pathology Mice Myofibroblasts Myofibroblasts - pathology Neoplasm Invasiveness Receptors, CXCR4 - metabolism Signal Transduction Stem cells Stromal cells Stromal Cells - metabolism Stromal Cells - pathology Transforming Growth Factor beta - metabolism Tumors Xenograft Model Antitumor Assays |
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Proceedings of the National Academy of Sciences - PNAS, 2010-11, Vol.107 (46), p.20009-20014 |
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Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs. |
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Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1013805107</identifier><identifier>PMID: 21041659</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Autocrine Communication ; Biological Sciences ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Breasts ; Cancer ; Carcinoma ; Cell Differentiation ; Chemokine CXCL12 - metabolism ; Epithelial cells ; Female ; Fibroblasts ; Humans ; Mammary Glands, Human - metabolism ; Mammary Glands, Human - pathology ; Mice ; Myofibroblasts ; Myofibroblasts - pathology ; Neoplasm Invasiveness ; Receptors, CXCR4 - metabolism ; Signal Transduction ; Stem cells ; Stromal cells ; Stromal Cells - metabolism ; Stromal Cells - pathology ; Transforming Growth Factor beta - metabolism ; Tumors ; Xenograft Model Antitumor Assays</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-11, Vol.107 (46), p.20009-20014</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-5fca3bf4118b7c377ef2638b4bd7637a1c232e730184ce19df386bb1508efc7b3</citedby><cites>FETCH-LOGICAL-c463t-5fca3bf4118b7c377ef2638b4bd7637a1c232e730184ce19df386bb1508efc7b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/46.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25748795$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25748795$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,734,787,791,892,27985,27986,54176,54178,58942,59175</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21041659$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kojima, Yasushi</creatorcontrib><creatorcontrib>Acar, Ahmet</creatorcontrib><creatorcontrib>Eaton, Elinor Ng</creatorcontrib><creatorcontrib>Mellody, Kieran T</creatorcontrib><creatorcontrib>Scheel, Christina</creatorcontrib><creatorcontrib>Ben-Porath, Ittai</creatorcontrib><creatorcontrib>Onder, Tamer T</creatorcontrib><creatorcontrib>Wang, Zhigang C</creatorcontrib><creatorcontrib>Richardson, Andrea L</creatorcontrib><creatorcontrib>Weinberg, Robert A</creatorcontrib><creatorcontrib>Orimo, Akira</creatorcontrib><title>Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.</description><subject>Animals</subject><subject>Autocrine Communication</subject><subject>Biological Sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Breasts</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Cell Differentiation</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>Epithelial cells</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Humans</subject><subject>Mammary Glands, Human - metabolism</subject><subject>Mammary Glands, Human - pathology</subject><subject>Mice</subject><subject>Myofibroblasts</subject><subject>Myofibroblasts - pathology</subject><subject>Neoplasm Invasiveness</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Signal Transduction</subject><subject>Stem cells</subject><subject>Stromal cells</subject><subject>Stromal Cells - metabolism</subject><subject>Stromal Cells - pathology</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNpVkcFuFCEcxonR2HX17Enlph7GwsAAc2nStN1q0sRD2zMBBrY0M8MKzCZ9Bt_GB_GZZLLrrnKB8P3-H1_4AHiL0ReMODndjCqVEyYCNeXiGVhg1OKK0RY9BwuEal4JWtMT8CqlR4RQ2wj0EpzUGFHMmnYBfp5POZjoRwvvrlfV719QjR1MOYZB9dDYvq86G_3WdtApk0OsMPx0e7mq8GeY_HpUvR_XsJuJBPODhXYb-in7MMLgYJ6GMrEpZiHP3KCGQcWng__wFJzXMehepZxegxdO9cm-2e9LcL-6urv4Wt18v_52cX5TGcpIrhpnFNGOYiw0N4Rz62pGhKa644xwhU1NassJwoIai9vOEcG0xg0S1hmuyRKc7Xw3kx5sZ-yYo-rlJvo5nAzKy_-V0T_IddjKum3JvJbg494ghh-TTVkOPs1_pUYbpiQFErQhjKFCnu5IE0NK0brDKxjJuUE5NyiPDZaJ9_-GO_B_KysA3APz5NGOS8pkPXdckHc75DGVxo4WDaeCt03RP-x0p4JU6-iTvL-tSwaEW4wZxeQPLyq4Zg</recordid><startdate>20101116</startdate><enddate>20101116</enddate><creator>Kojima, Yasushi</creator><creator>Acar, Ahmet</creator><creator>Eaton, Elinor Ng</creator><creator>Mellody, Kieran T</creator><creator>Scheel, Christina</creator><creator>Ben-Porath, Ittai</creator><creator>Onder, Tamer T</creator><creator>Wang, Zhigang C</creator><creator>Richardson, Andrea L</creator><creator>Weinberg, Robert A</creator><creator>Orimo, Akira</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</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><scope>5PM</scope></search><sort><creationdate>20101116</creationdate><title>Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts</title><author>Kojima, Yasushi ; Acar, Ahmet ; Eaton, Elinor Ng ; Mellody, Kieran T ; Scheel, Christina ; Ben-Porath, Ittai ; Onder, Tamer T ; Wang, Zhigang C ; Richardson, Andrea L ; Weinberg, Robert A ; Orimo, Akira</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-5fca3bf4118b7c377ef2638b4bd7637a1c232e730184ce19df386bb1508efc7b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Autocrine Communication</topic><topic>Biological Sciences</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Breasts</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Cell Differentiation</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>Epithelial cells</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Humans</topic><topic>Mammary Glands, Human - metabolism</topic><topic>Mammary Glands, Human - pathology</topic><topic>Mice</topic><topic>Myofibroblasts</topic><topic>Myofibroblasts - pathology</topic><topic>Neoplasm Invasiveness</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Signal Transduction</topic><topic>Stem cells</topic><topic>Stromal cells</topic><topic>Stromal Cells - metabolism</topic><topic>Stromal Cells - pathology</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kojima, Yasushi</creatorcontrib><creatorcontrib>Acar, Ahmet</creatorcontrib><creatorcontrib>Eaton, Elinor Ng</creatorcontrib><creatorcontrib>Mellody, Kieran T</creatorcontrib><creatorcontrib>Scheel, Christina</creatorcontrib><creatorcontrib>Ben-Porath, Ittai</creatorcontrib><creatorcontrib>Onder, Tamer T</creatorcontrib><creatorcontrib>Wang, Zhigang C</creatorcontrib><creatorcontrib>Richardson, Andrea L</creatorcontrib><creatorcontrib>Weinberg, Robert A</creatorcontrib><creatorcontrib>Orimo, Akira</creatorcontrib><collection>AGRIS</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kojima, Yasushi</au><au>Acar, Ahmet</au><au>Eaton, Elinor Ng</au><au>Mellody, Kieran T</au><au>Scheel, Christina</au><au>Ben-Porath, Ittai</au><au>Onder, Tamer T</au><au>Wang, Zhigang C</au><au>Richardson, Andrea L</au><au>Weinberg, Robert A</au><au>Orimo, Akira</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2010-11-16</date><risdate>2010</risdate><volume>107</volume><issue>46</issue><spage>20009</spage><epage>20014</epage><pages>20009-20014</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Author contributions: A.O. designed research; Y.K., A.A., E.N.E., K.T.M., C.S., and A.O. performed research; I.B.-P., T.T.O., Z.C.W., and A.L.R. contributed new reagents/analytic tools; Y.K., A.A., R.A.W., and A.O. analyzed data; and K.T.M., R.A.W., and A.O. wrote the paper.</notes><notes>Contributed by Robert A. Weinberg, September 17, 2010 (sent for review July 22, 2010)</notes><abstract>Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21041659</pmid><doi>10.1073/pnas.1013805107</doi><oa>free_for_read</oa></addata></record> |