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Review
. 2007 Jul 1;101(4):830-9.
doi: 10.1002/jcb.21186.

Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT?

Derek C Radisky  1 , Paraic A Kenny, Mina J Bissell
Affiliations
Review

Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT?

Derek C Radisky et al. J Cell Biochem. .

Abstract

Myofibroblasts produce and modify the extracellular matrix (ECM), secrete angiogenic and pro-inflammatory factors, and stimulate epithelial cell proliferation and invasion. Myofibroblasts are normally induced transiently during wound healing, but inappropriate induction of myofibroblasts causes organ fibrosis, which greatly enhances the risk of subsequent cancer development. As myofibroblasts are also found in the reactive tumor stroma, the processes involved in their development and activation are an area of active investigation. Emerging evidence suggests that a major source of fibrosis- and tumor-associated myofibroblasts is through transdifferentiation from non-malignant epithelial or epithelial-derived carcinoma cells through epithelial-mesenchymal transition (EMT). This review will focus on the role of EMT in fibrosis, considered in the context of recent studies showing that exposure of epithelial cells to matrix metalloproteinases (MMPs) can lead to increased levels of cellular reactive oxygen species (ROS) that stimulate transdifferentiation to myofibroblast-like cells. As deregulated MMP expression and increased cellular ROS are characteristic of both fibrosis and malignancy, these studies suggest that increased MMP expression may stimulate fibrosis, tumorigenesis, and tumor progression by inducing a specialized EMT in which epithelial cells transdifferentiate into activated myofibroblasts. This connection provides a new perspective on the development of the fibrosis and tumor microenvironments.

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Figures

Fig. 1
Fig. 1
Induction of fibrosis in breast and lung of MMP-3-transgenic mice. A: Accumulation of collagen around ducts of 15-day pregnant MMP-3-transgenic mice, assessed by Gomori's trichrome staining for total collagen (blue) (scale bar = 50 mm). B: Alveolar hyperplasia and collagen deposition characteristic of early fibrosis in newborn CCSP-rtTA/tet-MMP-3 transgenic mice induced to express MMP-3 for 7d in utero, assessed by Masson's trichrome stain (scale bar = 200 mm). A: Adapted from Thomasset et al., 1998.
Fig. 2
Fig. 2
Properties of MMP-3-induced EMT. A: MMP-3-treated SCp2 cells, stained for cytokeratins (red), vimentin (green), and DNA (blue) (scale bar = 50 μm). B: Marker transcript levels in cells treated with MMP-3 for 4 days; P < 0.01 for all altered expression levels. Adapted from Radisky et al., 2005.
Fig. 3
Fig. 3
MMP-3-induced ROS activate EMT. A: SCp2 cells treated with MMP-3 stimulate increased production of Rac1b, as assessed by Rac1 activity assay and Western blot with Rac1b-specific antibody. B: Exposure to MMP-3 activates redox-sensitive fluorescent dye DCFDA in Rac1/Rac1b-dependent fashion. C: MMP-3 treatment induces mitochondrial production of superoxide as shown by precipitation of nitrobluetetrazolium in cells treated with MMP-3 (b) as compared to untreated cells (a). D: MMP-3 treatment induces mitochondrial depolarization as shown by loss of punctuate red staining of the J-aggregate and increased diffuse green staining of the monomeric form in the MMP-3-treated cells (b) as compared to untreated (a). E–F: Exposure to H2O2 induces cell scattering (E) and invasiveness through Matrigel (F), as compared with MMP-3-treated cells. Scale bars for C–D, 10 μm; for E, 50 μm. G: MMP-3-induced upregulation of mesenchymal vimentin expression is inhibited by NAC and is reproduced by exposure to H2O2 or by expression of Rac1b. Adapted from Radisky et al., 2005.
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