ArticleOncotarget2017
Tumor-fibroblast interactions stimulate tumor vascularization by enhancing cytokine-driven production of MMP9 by tumor cells.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- p38 blockade reverses the immune suppressive tumor microenvironment in metastatic breast cancer.Research square · 2025Article
- Advances in targeting cancer-associated fibroblasts through single-cell spatial transcriptomic sequencing.Biomarker research · 2024Review
- The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy.Frontiers in cell and developmental biology · 2024Review
- Overexpression of FRA1 (Cells · 2023Article
- Suppression of triple-negative breast cancer aggressiveness by LGALS3BP via inhibition of the TNF-α-TAK1-MMP9 axis.Cell death discovery · 2023Article
- Pathophysiological Mechanisms Explaining the Association Between Low Skeletal Muscle Mass and Cognitive Function.The journals of gerontology. Series A, Biological sciences and medical sciences · 2022Review
- JUNB suppresses distant metastasis by influencing the initial metastatic stage.Clinical & experimental metastasis · 2021Article
- Biological effects of exosome derived from Cal27 on normal human gingival fibroblasts.Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology · 2021Article
- Effects of S100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A9 (S100A9) on matrix metalloproteinase (MMP) expression in nasopharyngeal carcinoma CNE-2 cells.Translational cancer research · 2021Article
- How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease.International journal of molecular sciences · 2021Review
- The Newly Synthetized Chalcone L1 Is Involved in the Cell Growth Inhibition, Induction of Apoptosis and Suppression of Epithelial-to-Mesenchymal Transition of HeLa Cells.Molecules (Basel, Switzerland) · 2021Article
- The vascular landscape of human cancer.The Journal of clinical investigation · 2021Article
- Profiling the Expression of Circulating Acute-Phase Proteins, Cytokines, and Checkpoint Proteins in Patients with Severe Trauma: A Pilot Study.Journal of inflammation research · 2021Article
- Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer.Frontiers in oncology · 2021Review
- Article
- Blockade of p38 kinase impedes the mobilization of protumorigenic myeloid populations to impact breast cancer metastasis.International journal of cancer · 2020Article
- Molecular evaluation of chronic restrain stress in mice model of non metastatic fibrosarcoma.Journal of molecular histology · 2020Article
- Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure.Laboratory investigation; a journal of technical methods and pathology · 2020Article
- TAK1 signaling regulates p53 through a mechanism involving ribosomal stress.Scientific reports · 2020Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Advance-stage breast carcinomas include significant amounts of fibroblasts and infiltrating immune cells which have been implicated in tumor growth, recurrence, and response to therapy. The present study investigated the contribution of fibroblasts to tumor growth using direct tumor-fibroblast co-cultures and tumor xenograft models. Our findings revealed that fibroblasts enhance breast carcinoma growth by promoting the tumor vasculature via the MMP9-dependent mechanism. In tumor-fibroblast co-cultures, fibroblasts increased expression of TGF-β, TNF, and IL-1β cytokines in tumor cells. These cytokines cooperatively induced expression of matrix metalloproteinase MMP9 in tumor cells. Knockdown of MMP9 by shRNA significantly reduced tumor vascularization induced by fibroblasts. Mechanistically, our findings argue that expression of MMP9 in tumor cellsis regulated by crosstalk of TGF-β with TNF and/or IL-1β cytokines. The mechanism of this cooperative response did not involve cross-activation of the canonical signaling pathways as TGF-β did not activate RELA/p65 signaling, while TNF did not affect SMAD signaling. Instead, TGF-β and TNF cytokines co-stimulated MAP kinases and expression of JUN and JUNB, AP1 transcription factor subunits, which together with RELA/p65 were essential for the regulation of MMP9. Depletion of JUN and JUNB or RELA in tumor cells blocked the cooperative induction of MMP9 by the cytokines. Thus, our studies uncovered a previously unappreciated role of tumor-fibroblast interactions in the stimulation of tumor angiogenesis, and an essential role of the MAPK-AP1 axis in the cooperative up-regulation of the angiogenic driver MMP9 by cytokine crosstalk.
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Registered trials
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