Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fib...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2011
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| Online Access: | http://hdl.handle.net/1721.1/64942 https://orcid.org/0000-0002-0895-3557 |
| _version_ | 1826199944230338560 |
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| author | Kojima, Yasushi Acar, Ahmet Eaton, Elinor Ng Mellody, Kieran T. Scheel, Christina Ben-Porath, Ittai Onder, Tamer T. Wang, Zhigang C. Richardson, Andrea L. Weinberg, Robert A. Orimo, Akira |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kojima, Yasushi Acar, Ahmet Eaton, Elinor Ng Mellody, Kieran T. Scheel, Christina Ben-Porath, Ittai Onder, Tamer T. Wang, Zhigang C. Richardson, Andrea L. Weinberg, Robert A. Orimo, Akira |
| author_sort | Kojima, Yasushi |
| collection | MIT |
| description | Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β [TGF-beta] and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β [TGF-beta] and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs. |
| first_indexed | 2024-09-23T11:28:17Z |
| format | Article |
| id | mit-1721.1/64942 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:28:17Z |
| publishDate | 2011 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/649422022-10-01T03:50:27Z Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts Kojima, Yasushi Acar, Ahmet Eaton, Elinor Ng Mellody, Kieran T. Scheel, Christina Ben-Porath, Ittai Onder, Tamer T. Wang, Zhigang C. Richardson, Andrea L. Weinberg, Robert A. Orimo, Akira Massachusetts Institute of Technology. Department of Biology Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology) Weinberg, Robert A. Onder, Tamer T. Weinberg, Robert A. Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β [TGF-beta] and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β [TGF-beta] and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs. National Cancer Institute (U.S.) (Grant R21CA87081-02) National Institutes of Health (U.S.) (Grant P01 CA080111) National Institutes of Health (U.S.) (Grant R01 CA078461) Virginia and D.K. Ludwig Fund for Cancer Research Breast Cancer Research Foundation Cancer Research UK (Grant C147/A6058) 2011-07-20T20:31:36Z 2011-07-20T20:31:36Z 2010-11 2010-09 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/64942 Kojima, Y. et al. “Autocrine TGF- and Stromal Cell-derived Factor-1 (SDF-1) Signaling Drives the Evolution of Tumor-promoting Mammary Stromal Myofibroblasts.” Proceedings of the National Academy of Sciences 107.46 (2010) : 20009-20014. https://orcid.org/0000-0002-0895-3557 en_US http://dx.doi.org/10.1073/pnas.1013805107 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Kojima, Yasushi Acar, Ahmet Eaton, Elinor Ng Mellody, Kieran T. Scheel, Christina Ben-Porath, Ittai Onder, Tamer T. Wang, Zhigang C. Richardson, Andrea L. Weinberg, Robert A. Orimo, Akira Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title | Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title_full | Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title_fullStr | Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title_full_unstemmed | Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title_short | Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts |
| title_sort | autocrine tgf beta and stromal cell derived factor 1 sdf 1 signaling drives the evolution of tumor promoting mammary stromal myofibroblasts |
| url | http://hdl.handle.net/1721.1/64942 https://orcid.org/0000-0002-0895-3557 |
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