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VEGF-A and Tenascin-C produced by S100A4 + stromal cells are important for metastatic colonization
Open accessAbstract
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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“VEGF expression by stromal cells can drive angiogenesis15,114.”
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“S100a4 is used as a marker of EMT and mesenchymal cells and its function is critical for breast cancer metastasis (17-22).”
Self-citationCancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment
Ganguly, D., Chandra, R., Karalis, J. D., Teke, M. E., Aguilera, T. A., Maddipati, R., Wachsmann, M., Ghersi, D., Siravegna, G., Zeh, H. J., et al. (2020) · Cancers · doi:10.3390/cancers12092652 · Cited by 130
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“including such as α-SMA, fibroblast activation protein (FAP), fibroblast specific protein (FSP)-1, and platelet-derived growth factor receptor (PDGFR)-α/β (19, 77, 78).”
BackgroundDecellularized Extracellular Matrix for Cancer Research
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“For the purpose of detailed investigations, genetically mutated animals and cells have been used [14,16].”
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“In contrast, upon investigating why some cancers are metastatic-incompetent through comparing parental MDA-MB-231 and the human prostate cancer cell line PC3 with their more metastatic counterparts LM2 and PCRM-LN4, respectively, TSP1 expression was shown to be induced in bone marrowderived CD11b Gr1 myeloid cells and…”
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“However, several reports have recently revealed that the ECM proteins periostin and TNC play key roles as metastasis niche components for tumour-initiating cells that invade the lungs (Figure 1A; Oskarsson et al , 2011; O’Connell et al , 2011; Malanchi et al , 2012).”
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“Meanwhile, stromal TN-C from S100A4+ fibroblasts is also necessary and stimulative for the metastasis colonization [17].”
InfluentialS100 proteins as therapeutic targets
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S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction
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The role of cancer-associated fibroblasts in tumorigenesis of gastric cancer
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“FSP1CAFs promote tumor metastasis and immune evasion in many tumors, including GC [31, 32].”
BackgroundRoles of Wnt Target Genes in the Journey of Cancer Stem Cells
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Distinct prognostic values of S100 mRNA expression in breast cancer
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“Furthermore, depletion of S100A4 + stromal cells significantly reduced metastatic potential of orthotopic mammary tumor without affecting primary tumor growth 30 .”
Metadata
- 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
- 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
- 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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