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To study the contribution of S100A4\n            <jats:sup>+<\/jats:sup>\n            stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the\n            <jats:italic>S100A4<\/jats:italic>\n            promoter to specifically ablate S100A4\n            <jats:sup>+<\/jats:sup>\n            stromal cells. Depletion of S100A4\n            <jats:sup>+<\/jats:sup>\n            stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4\n            <jats:sup>+<\/jats:sup>\n            stromal cells are attributable to local non\u2013bone marrow-derived S100A4\n            <jats:sup>+<\/jats:sup>\n            cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4\n            <jats:sup>+<\/jats:sup>\n            fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4\n            <jats:sup>+<\/jats:sup>\n            fibroblast-derived VEGF-A in metastasis was established by examining\n            <jats:italic>Tenascin-C<\/jats:italic>\n            null mice and transgenic mice expressing Cre recombinase under control of the\n            <jats:italic>S100A4<\/jats:italic>\n            promoter crossed with mice carrying\n            <jats:italic>VEGF-A<\/jats:italic>\n            alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4\n            <jats:sup>+<\/jats:sup>\n            fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4\n            <jats:sup>+<\/jats:sup>\n            fibroblasts in providing the permissive \u201csoil\u201d for metastatic colonization, a challenging step in the metastatic cascade.\n          <\/jats:p>","DOI":"10.1073\/pnas.1109493108","type":"journal-article","created":{"date-parts":[[2011,9,13]],"date-time":"2011-09-13T06:44:44Z","timestamp":1315896284000},"page":"16002-16007","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":304,"title":["VEGF-A and Tenascin-C produced by S100A4\n            <sup>+<\/sup>\n            stromal cells are important for metastatic colonization"],"prefix":"10.1073","volume":"108","author":[{"given":"Joyce T.","family":"O'Connell","sequence":"first","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Vesselina G.","family":"Cooke","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Brian A.","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Ankit I.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Valerie S.","family":"LeBleu","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Rajan","family":"Dewar","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"},{"name":"Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115;"}]},{"given":"Rafael M.","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hospital A. C. Camargo, Fundacao Antonio Prudente, 01509-010, Sao Paulo, Brazil;"}]},{"given":"Ricardo R.","family":"Brentani","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hospital A. C. Camargo, Fundacao Antonio Prudente, 01509-010, Sao Paulo, Brazil;"}]},{"given":"Murray B.","family":"Resnick","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rhode Island Hospital, Providence, RI 02903;"}]},{"given":"Eric G.","family":"Neilson","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37215; and"}]},{"given":"Michael","family":"Zeisberg","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, and"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, MA 02215"}]}],"member":"341","published-online":{"date-parts":[[2011,9,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/S0140-6736(96)91015-6","article-title":"The war on cancer","volume":"347","author":"Sporn MB","year":"1996","unstructured":"MB Sporn, The war on cancer. 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Eur J Cancer 46, 1177\u20131180 (2010).","journal-title":"Eur J Cancer"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1038\/sj.bjc.6602613","article-title":"The metastasis associated protein S100A4: Role in tumour progression and metastasis","volume":"92","author":"Helfman DM","year":"2005","unstructured":"DM Helfman, EJ Kim, E Lukanidin, M Grigorian, The metastasis associated protein S100A4: Role in tumour progression and metastasis. Br J Cancer 92, 1955\u20131958 (2005).","journal-title":"Br J Cancer"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/ijc.22850","article-title":"Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer","volume":"121","author":"Cabez\u00f3n T","year":"2007","unstructured":"T Cabez\u00f3n, et al., Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. 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