Tumor-fibroblast interactions stimulate tumor vascularization by enhancing cytokine-driven production of MMP9 by tumor cells
| Autor: | Alexander Truskinovsky, Amy Beattie, Michelle Limoge, Andrei V. Bakin, Alfiya Safina, Lauren Kapus |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Apoptosis Cell Communication SMAD MMP9 Mice Cancer-Associated Fibroblasts Transforming Growth Factor beta Neoplasms TGF-beta Cells Cultured Neovascularization Pathologic MAP Kinase Kinase Kinases 3. Good health AP-1 transcription factor Cytokine Matrix Metalloproteinase 9 Oncology Cytokines Female Tumor necrosis factor alpha Inflammation Mediators Signal transduction Signal Transduction Research Paper JUNB 03 medical and health sciences breast cancer Cell Line Tumor fibroblasts matrix metalloproteinase-9 TGF beta signaling pathway medicine Animals Humans Cell Proliferation Tumor Necrosis Factor-alpha business.industry Transcription Factor RelA tumor angiogenesis Xenograft Model Antitumor Assays Coculture Techniques Rats body regions Disease Models Animal 030104 developmental biology Immunology Cancer research business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.16022 |
| Popis: | // Michelle Limoge 1 , Alfiya Safina 3 , Amy Beattie 4 , Lauren Kapus 1 , Alexander M. Truskinovsky 2 and Andrei V. Bakin 1 1 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA 2 Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York, USA 3 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA 4 University at Buffalo School of Medicine, Buffalo, New York, USA Correspondence to: Andrei V. Bakin, email: // Keywords : fibroblasts, matrix metalloproteinase-9, tumor angiogenesis, TGF-beta, breast cancer Received : February 10, 2017 Accepted : February 24, 2017 Published : March 08, 2017 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. |
| Databáze: | OpenAIRE |
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