Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 38, Pages 16002-16007Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1109493108
Keywords
stromal fibroblasts; metastasis-associated fibroblasts; tumor microenvironment; metastatic microenvironment
Categories
Funding
- National Institutes of Health [DK55001, CA125550, CA155370, CA151925, DK81687, DK46282, CA68485, DK074558]
- American Society of Nephrology Carl W. Gottschalk Scholar
- Beth Israel Deaconess Medical Center and Harvard Medical School
- National Institutes of Health Cell and Developmental Biology Training [GM07226]
- Department of Defense Breast Cancer Predoctoral Traineeship [BC083229]
- Stop and Shop Pediatric Brain Tumor Foundation
- National Institutes of Health Training [2T32HL007374-32]
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [5F32DK082119-02]
- National Institutes of Health Research Training [2T32DK007760-11]
- CDMRP [544583, BC083229] Funding Source: Federal RePORTER
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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.
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