Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
Author(s)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; ... Show more Show less
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Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
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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.
DepartmentLudwig Center for Molecular Oncology; Massachusetts Institute of Technology. Department of Biology
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences (U.S.)
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.
Final published version