title: VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization.
abstract: Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4(+) stromal cells are attributable to local non-bone marrow-derived S100A4(+) cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4(+) 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(+) fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4(+) 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(+) fibroblasts in providing the permissive "soil" for metastatic colonization, a challenging step in the metastatic cascade.
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joyce T
authors.initials: JT
authors.lastname: O'Connell
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacDonald
authors.forename: Ankit I
authors.initials: AI
authors.lastname: Mehta
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.forename: Rajan
authors.initials: R
authors.lastname: Dewar
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rocha
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Brentani
authors.forename: Murray B
authors.initials: MB
authors.lastname: Resnick
authors.forename: Eric G
authors.initials: EG
authors.lastname: Neilson
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D019063:Tenascin; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir