Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts

Yasushi Kojima, Ahmet Acar, Elinor Ng Eaton, Kieran T. Mellody, Christina Scheel, Ittai Ben-Porath, Tamer T. Onder, Zhigang C. Wang, Andrea L. Richardson, Robert A. Weinberg, Akira Orimo

Research output: Contribution to journalArticlepeer-review

Abstract

Much interest is currently focused on the emerging role of tumorstroma 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.

Original languageEnglish (US)
Pages (from-to)20009-20014
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number46
DOIs
StatePublished - Nov 16 2010
Externally publishedYes

Keywords

  • Alpha-smooth muscle actin
  • CXCR4
  • Smad
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

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