Cited by 348S100 Proteins and AnnexinsCancer Cells and MetastasisMechanisms of cancer metastasis

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

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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·2011·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1109493108PMC PMC3179047

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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.

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Authors: O'Connell, J. T., Sugimoto, H., Cooke, V. G., MacDonald, B. A., Mehta, A. I., LeBleu, V. S., Dewar, R., Rocha, R. M., Brentani, R. R., Resnick, M. B., Neilson, E. G., Zeisberg, M., & Kalluri, R.
Affiliations: Division of Matrix Biology, Department of Medicine, and
Beth Israel Deaconess Medical Center (US)
AC Camargo Hospital (BR)
Department of Oncology, Hospital A. C. Camargo, Fundacao Antonio Prudente, 01509-010, Sao Paulo, Brazil;
Rhode Island Hospital (US)
Vanderbilt University (US)
Harvard University (US)
Corresponding author: Sugimoto, Hikaru
Kalluri, Raghu
ORCID: Sugimoto, Hikaru
MacDonald, Brian A.
Mehta, Ankit I.
LeBleu, Valerie S.
Dewar, Rajan
Rocha, Rafael M.
Resnick, Murray B.
Neilson, Eric G.
Zeisberg, Michael
Kalluri, Raghu
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2011-09-12
Volume: 108
Issue: 38
Pages: 16002-16007
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1109493108
PMC: PMC3179047
OpenAlex: W2043664496
Cited by: 348
References: 38
Citations by year: 2026: 8 · 2025: 13 · 2024: 24 · 2023: 23 · 2022: 31 · 2021: 33 · 2020: 37 · 2019: 22 · 2018: 24 · 2017: 18 · 2016: 20 · 2015: 26 · 2014: 24 · 2013: 26 · 2012: 16
FWCI: 8.84
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1f32dk082119-01, 5t32hl007374-41)
National Heart, Lung, and Blood Institute (T32‐HL007374, 2T32HL007374-32)
National Cancer Institute (U01CA151925, CA 125550, R01CA155370, CA68485, CA 155370, CA 151925, R01CA125550, P30CA068485)
National Institute of General Medical Sciences (GM07226, T32GM007226)
National Institute of Diabetes and Digestive and Kidney Diseases (R03DK081687, F32 DK082119, T32DK007760, R01DK046282, DK46282, K08DK074558, DK-55001, DK81687, 5F32DK082119-02, DK074558, R01DK055001)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords: S100A4, stromal cells, tenascin-C, VEGF-A, metastatic colonization, tumor microenvironment, fibroblasts, tumor stroma, angiogenesis, extracellular matrix, apoptosis, bone marrow transplantation, metastasis
MeSH terms: S100 Calcium-Binding Protein A4, Animals, Female, Fibroblasts, Humans, Immunohistochemistry, Male, Mice, Transgenic, Neoplasm Metastasis, Neoplasms, S100 Proteins, Thymidine Kinase, Ganciclovir, Extracellular Matrix Proteins, Stromal Cells, Mice, Knockout, Tenascin, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Green Fluorescent Proteins, Mice, Tumor Microenvironment

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

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