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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.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [114]
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“S100A4-positive cells, which did not express the CD45 immune cell marker, were also detected in the metastatic microenvironment of human breast cancers (44).”
BackgroundMethodUrooj, T., Wasim, B., Mushtaq, S., Shah, S. N. N., & Shah, M. (2019) · Current Cancer Drug Targets · doi:10.2174/1568009620666191220151856 · Cited by 39
Fibroblast subtypes define a metastatic matrisome in breast cancer
Brechbuhl, H. M., Barrett, A. S., Kopin, E. G., Hagen, J., Han, A., Gillen, A. E., Finlay-Schultz, J., Cittelly, D. M., Owens, P., Horwitz, K. B., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.130751 · Cited by 40
“Although more studies are required to directly link the invasion phenotype with direct EGFR activaion by TNC, our results recapitulate previous reports correlating increased TNC expression to higher risk for invasive breast cancer and several other cancer types (39-43).”
ResultGeleta, B., Shehadeh-Tout, F., Lim, S. C., Sahni, S., Jansson, P. J., Apte, M. V., Richardson, D. R., & Kovačević, Ž. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101608 · Cited by 39
Mammadova‐Bach, E., Mangin, P., Lanza, F., & Gachet, C. (2015) · Hämostaseologie · doi:10.5482/hamo-14-11-0065 · Cited by 38
“Moreover, cancer associated fibroblasts producing TNC and VEGF have been reported to provide the permissive “soil” for metastatic colonization (85).”
BackgroundTajaldini, M., Poorkhani, A., Amiriani, T., Amiriani, A., Javid, H., Aref, P., Ahmadi, F., Sadani, S., & Khori, V. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175991 · Cited by 38
It’s all about the base: stromal cells are central orchestrators of metastasis
Monteran, L., Zait, Y., & Erez, N. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.11.004 · Cited by 40
Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives
Toledo, B., Picon‐Ruiz, M., Marchal, J. A., & Perán, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415576 · Cited by 41
“S100A4+ CAFs promote tumour metastasis through secretion of VEGF-A and Tenascin-C (TN-C) [90].”
BackgroundInfluentialStromal biomarkers in breast cancer development and progression
Rudnick, J. A., & Kuperwasser, C. (2012) · Clinical & Experimental Metastasis · doi:10.1007/s10585-012-9499-8 · Cited by 38
“Recent findings demonstrate TN-C secretion by stromal fibroblasts [17] as well as breast tumor cells [48] may support metastatic colonization of tumor cells but not significantly impact primary tumor growth.”
BackgroundXu, T., Liu, Z., Huang, L., Jing, J., & Liu, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1057850 · Cited by 38
“In addition, CAFs promote OC metastasis by secreting VEGF-A and tenascin-c (86).”
BackgroundCross-Talk Between Cancer and Its Cellular Environment—A Role in Cancer Progression
Turlej, E., Domaradzka, A., Radzka, J., Drulis‐Fajdasz, D., Kulbacka, J., & Gizak, A. (2025) · Cells · doi:10.3390/cells14060403 · Cited by 47
Translation of cancer immunotherapy from the bench to the bedside
Guo, Q., Huang, F., Gonçalves, C., Rincon, S. V. D., & Miller, W. H. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2019.03.001 · Cited by 35
Petersen, E. V., Chudakova, D. A., Skorova, E., Anikin, V., Reshetov, I. V., & Mynbaev, O. A. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.575569 · Cited by 38
Spatial organization of the tenascin-C microenvironment in experimental and human cancer
Spenlé, C., Gasser, I., Saupe, F., Janssen, K., Arnold, C., Klein, A., van der Heyden, M., Mutterer, J., Méchine‐Neuville, A., Chenard, M., et al. (2015) · Cell Adhesion & Migration · doi:10.1080/19336918.2015.1005452 · Cited by 38
“Tumor cells contribute to expression of tenascin-C in tracks as a microenvironment for stromal cells Stromal cells are a major source of TNC in the lung metastatic breast murine 4T1 breast cancer grafting model.(27) Moreover, during lung metastasis in the MDA-MB231 xenograft model tumor cell-derived TNC was crucial fo…”
BackgroundZhang, X., Zhu, R., Yu, D., Wang, J., Yan, Y., & Xu, K. (2023) · Cell Proliferation · doi:10.1111/cpr.13592 · Cited by 35
Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets
Lv, K., & He, T. (2024) · Molecular Biomedicine · doi:10.1186/s43556-024-00233-8 · Cited by 36
Chiovaro, F., Martina, E., Bottos, A., Scherberich, A., Hynes, N. E., & Chiquet‐Ehrismann, R. (2015) · International Journal of Cancer · doi:10.1002/ijc.29565 · Cited by 33
The role of autophagy in colorectal cancer: Impact on pathogenesis and implications in therapy
Mahgoub, E., Taneera, J., Sulaiman, N. D., & Saber-Ayad, M. M. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.959348 · Cited by 33
“Autocrine VEGF released from endothelial cells and gastrin-releasing peptide (GRP) secreted by tumors promote angiogenesis, endothelial survival, and proliferation of endothelial cells by inhibiting autophagy (101).”
BackgroundInfluentialCancer‐associated fibroblasts: Is it a key to an intricate lock of tumorigenesis?
Aden, D., Zaheer, S., Ahluwalia, H., & Ranga, S. (2023) · Cell Biology International · doi:10.1002/cbin.12004 · Cited by 33
“…kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells which are likely fibroblasts in this setting, showed that ablation of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth (O'Connell et al., 2011).”
BackgroundInfluentialS100A4 promotes colon inflammation and colitis-associated colon tumorigenesis
Zhang, J., Hou, S., Gu, J. H., Tian, T., Yuan, Q., Jia, J., Qin, Z., & Chen, Z. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1461301 · Cited by 32
“metastatic colonization by regulating matrix protein tenascin-C and growth factor vascular endothelial growth factor (VEGF)A.(32) In previous studies, we found an additional mechanism of”
BackgroundCD36 and CD97 in Pancreatic Cancer versus Other Malignancies
Tănase, C., Gheorghișan-Gălățeanu, A.-A., Popescu, I. D., Mihai, S., Codrici, E., Albulescu, R., & Hinescu, M. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165656 · Cited by 32
Tenascin-C expression in the lymph node pre-metastatic niche in muscle-invasive bladder cancer
Silvers, C. R., Messing, E. M., Miyamoto, H., & Lee, Y. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01554-z · Cited by 32
“While tenascin-C produced by both cancer cells [21] and stromal cells [7] has previously been shown to be a critical component of the microenvironment once metastasising cancer cells arrive, our work is the first to our knowledge to establish stromal tenascin-C induction as a feature of the pre-metastatic niche.”
BackgroundProductive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis
Aziz, M. A. A. E., Agarwal, K., Dasari, S., & Mitra, A. K. (2019) · Cancers · doi:10.3390/cancers11101608 · Cited by 31
“At the metastatic niche, fibroblast-specific protein 1 (FSP1)-positive cells have also been found to enhance cancer cell metastasis via vascular endothelial growth factor A (VEGFA) secretion, and depletion of these cells significantly reduces the metastatic colonization, while primary tumor growth remains unaffected […”
BackgroundLv, X., Wang, B., Liu, K., Li, M. J., Yi, X., & Wu, X. (2024) · iScience · doi:10.1016/j.isci.2024.110064 · Cited by 31
“35,37,38,54 Considering that VEGF-mediated signaling occurs in tumor cells and contributes to pivotal aspects of tumorigenesis, such as the function of CSCs and tumor initiation, the observed reduction in cell migration and self-renewal abilities after VEGFR knockdown un-derscores the…”
Medeiros, B., Goodale, D. B., Postenka, C. O., Lowes, L. E., Kiser, P. K., Hearn, S., Salmond, N., Williams, K. C., & Allan, A. L. (2020) · Cancers · doi:10.3390/cancers12010172 · Cited by 31
“In a malignant state, CD117+ VEGFR1+ HPCs circulate and bind to areas of increased fibronectin deposition, inducing the release of the proteinase MMP9 and resulting in the breakdown of the basement membrane to promote recruitment and colonization of cancer cells [15].”
BackgroundInfluentialMukaida, N., Zhang, D., & Sasaki, S. (2020) · Cancers · doi:10.3390/cancers12102896 · Cited by 34
“CAFs produce the most potent angiogenic factor, VEGF, abundantly [63].”
BackgroundTenascin-C Signaling in melanoma
Shao, H., Kirkwood, J. M., & Wells, A. H. (2014) · Cell Adhesion & Migration · doi:10.4161/19336918.2014.972781 · Cited by 31
Priming cancer cells for drug resistance: role of the fibroblast niche
Fang, W. B., Yao, M., & Cheng, N. (2014) · Frontiers in Biology · doi:10.1007/s11515-014-1300-8 · Cited by 31
“FSP1 expressing CAFs in the lung support metastatic colonization of 4T1 mammary carcinoma cells through tenascin C expression (O’Connell et al., 2011).”
BackgroundAlguacil-Núñez, C., Ferrer-Ortiz, I., García-Verdú, E., López-Pirez, P., Llorente-Cortijo, I. M., & Sainz, B. (2018) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2018.02.015 · Cited by 29
Activated Tumor-infiltrating Fibroblasts Predict Worse Prognosis in Breast Cancer Patients
Hu, G., Xu, F., Zhong, K., Wang, S., Huang, L., & Chen, W. (2018) · Journal of Cancer · doi:10.7150/jca.28054 · Cited by 30
“For instance, FAP-α+ fibroblasts have been thought to be involved in modulation of ECM and tumor cell invasion through increasing levels of fibronectin and collagen fiber organization [33]; while PDGFR-β+ fibroblasts were shown to be associated with metastastic spread and high interstitial fluid pressure [34, 35], and…”
BackgroundEngineering strategies to capture the biological and biophysical tumor microenvironment in vitro
Tan, M. L., Lu, L., & Fischbach, C. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113852 · Cited by 31
S100A4 protects the myocardium against ischemic stress
Doroudgar, S., Quijada, P. J., Konstandin, M. H., et al. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.10.001 · Cited by 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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