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.
Original language | English (US) |
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Pages (from-to) | 16002-16007 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 108 |
Issue number | 38 |
DOIs | |
State | Published - Oct 20 2011 |
Keywords
- Metastasis-associated fibroblasts
- Metastatic microenvironment
- Stromal fibroblasts
- Tumor microenvironment
ASJC Scopus subject areas
- General