VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.16002-16007
• Main Authors: O'Connell, Joyce T, Sugimoto, Hikaru, Cooke, Vesselina G, MacDonald, Brian A, Mehta, Ankit I, LeBleu, Valerie S, Dewar, Rajan, Rocha, Rafael M, Brentani, Ricardo R, Resnick, Murray B, Neilson, Eric G, Zeisberg, Michael, Kalluri, Raghu
• Format: Article
• Language: English
• Subjects: alleles; Animals; apoptosis; Biological Sciences; Bone marrow; bone marrow transplant; Breast cancer; Cancer; Cell growth; Cell Line, Tumor; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Ganciclovir - pharmacology; Gene Expression Profiling; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Immunohistochemistry; Lungs; Male; Metastasis; Mice; Mice, Knockout; Mice, Transgenic; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nodules; Oligonucleotide Array Sequence Analysis; patients; prognosis; Proteins; Rodents; S100 Calcium-Binding Protein A4; S100 Proteins - genetics; S100 Proteins - metabolism; Stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Tenascin - genetics; Tenascin - metabolism; thymidine kinase; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Tumor Microenvironment - drug effects; Tumors; vascular endothelial growth factor A; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1109493108

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.