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 angiogenesis.
“VEGF expression by stromal cells can drive angiogenesis15,114.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [114]
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“Subsequently as the micrometastasis grows, reactive stroma takes over as a source of TNC and thereby maintains the viability of cancer cells.(36,92) Importantly, the expression of TNC in breast cancer cells is further induced under conditions that enrich for stem cell properties, such as in spheroid cultures,(36) a ph…”
BackgroundTenascin-C and integrins in cancer
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“Several studies support that other factors such as BRD4, IL-30, serpin –E2, VEGF-A and Tenascin-C regulate breast cancer dissemination and metastatic colonization [3, 4, 71, 88] in the TME.”
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Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target
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“In an orthotopic mouse model of breast cancer, they show that the production of tenascin by these FSP-1+ CAFs promotes VEGF-A-mediated angiogenesis and metastasis [55].”
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“Previous studies have identified cancer-associated fibroblasts as a major source of Tnc in tumors (39), but whether stroma-derived Tnc has a role in tumor progression in this model is unclear.”
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“S100A4+ cells depletion mice model [68]) seem to be valuable tools for exploring the permissive “soil” effect of CAFs on radiotherapy.”
BackgroundCancer-associated fibroblasts: The chief architect in the tumor microenvironment
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“Other secretory functions of CAFs, such as vascular endothelial growth factor (VEGF) synthesis by the stromal cells, can lead to angiogenesis (O’Connell et al., 2011; Fukumura et al., 1998).”
BackgroundTenascin C Promiscuously Binds Growth Factors via Its Fifth Fibronectin Type III-Like Domain
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“Several observations indicate that inflammatory factors secreted by CAFs participate in this transformation and Wnt pathway [47–50].”
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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 122 · see citing works
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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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“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…”
BackgroundInfluentialCancer-Associated Fibroblasts Promote Proliferation of Endometrial Cancer Cells
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BackgroundThe pre-metastatic niche in lymph nodes: formation and characteristics
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InfluentialS100 proteins as therapeutic targets
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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
- 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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