MMP13 in PyMT Tumor Fibroblast Figure 7. Absence of MMP13 influences fibrillar collagen in the MMTV-PyMT tumor stroma. (A) Tissue sections from MMTV-PyMT;Mmp13+/+ (a-d) and MMTV-PyMT;Mmp132/2 (e–h) tumors stained with haematoxylin and eosin (a,e) or picrosirius red (b,f), the latter illuminated with linearly polarized light. Color threshold images of total collagen (c,g) and thin collagen fibers (d,h) of the images in b and f, respectively. (B) Box plots of total collagen (left), thin collagen fibers (middle) and the ratio between thin collagen fibers and total collagen (right, *p,0.01, t-test) measured in MMTV- PyMT;Mmp13+/+ (gray boxes, n = 26) and MMTV-PyMT;Mmp132/2 (white boxes, n = 21) tumors as shown in the A panel. doi:10.1371/journal.pone.0002959.g007 It is unknown what induces Mmp13 in the breast carcinoma- associated myofibroblasts, but the restricted expression of Mmp13 in dense fibrous stromal septae within the central parts of the invasive MMTV-PyMT tumors suggests a locally expressed tumor-cell derived factor. In vitro studies have shown that IL-1a, IL-1b, and transforming growth factor-b1, in particular, can induce Mmp13 mRNA expression in fibroblasts [45]. Interestingly, TGFb signaling through fibroblast-expressed TGFb receptor type II has a considerable impact on tumor growth [46]. Mmp13 mRNA expressing myofibroblasts are often found in the tumor core close to areas with necrosis suggesting that MMP13 may be upregulated in response to hypoxia for stimulation of angiogenesis. PLoS ONE | www.plosone.org 9 August 2008 | Volume 3 | Issue 8 | e2959