Autocrine TGF-β 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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (46), p.20009-20014
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Animals Autocrine Communication Biological Sciences Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Breasts Cancer Carcinoma Cell Differentiation Chemokine CXCL12 - metabolism Epithelial cells Female Fibroblasts Humans Mammary Glands, Human - metabolism Mammary Glands, Human - pathology Mice Myofibroblasts Myofibroblasts - pathology Neoplasm Invasiveness Receptors, CXCR4 - metabolism Signal Transduction Stem cells Stromal cells Stromal Cells - metabolism Stromal Cells - pathology Transforming Growth Factor beta - metabolism Tumors Xenograft Model Antitumor Assays
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Summary:	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 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 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.
ISSN:	0027-8424 1091-6490