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

Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16002-7. doi: 10.1073/pnas.1109493108. Epub 2011 Sep 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Ganciclovir / pharmacology
  • Gene Expression Profiling
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oligonucleotide Array Sequence Analysis
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / genetics
  • S100 Proteins / metabolism*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Tenascin / genetics
  • Tenascin / metabolism*
  • Thymidine Kinase / genetics
  • Thymidine Kinase / metabolism
  • Tumor Microenvironment / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Extracellular Matrix Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Tenascin
  • Vascular Endothelial Growth Factor A
  • Green Fluorescent Proteins
  • Thymidine Kinase
  • Ganciclovir

Associated data

  • GEO/GSE31711