MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma

Abstract

Matrix metalloproteinases (MMPs) such as MMP13 promote tumour growth and progression by mediating extracellular matrix (ECM) reorganization and regulating the biological activity of cytokines. Using Mmp13-/- mice, we demonstrate an essential role of this single collagenase for highly malignant and invasive growth in skin squamous cell carcinoma (SCC). Lack of host MMP13 strongly impaired tumour growth of malignant SCC cells, leading to small, mostly avascular cysts. While initial stromal activation in tumour transplants of Mmp13+/+ and Mmp13-/- animals was similar, MMP13 was essential for maintenance of angiogenesis and for invasion. MMP13 was induced in fibroblasts of the wild-type animals at the onset of invasion and correlated with a strong increase in vascular endothelial growth factor (VEGF) protein and its association with vascular endothelial growth factor receptor-2 on endothelial cells in invasive areas. In contrast, VEGF protein in the stroma was barely detectable and tumour invasion was downregulated in Mmp13-/- animals, despite ongoing VEGF messenger RNA expression. Taken together with in vitro data showing the release of VEGF from the ECM by MMP13 expressing fibroblasts, these data strongly suggest a crucial role of MMP13 in promoting angiogenesis via releasing VEGF from the ECM and thus allowing the invasive growth of the SCC cells.

Quantitative Real-Time RT-PCR of ITGA7, SVEP1, TNS1, LPHN3, SEMA3G, KLB and MMP13 mRNA Expression in Breast Cancer

“…MMP13 or collagenase-3 is a member of the matrix metalloproteinase family of endopeptidases that have potent degrading activity for degrading the major protein components of the extracellular matrix and basement membranes of the cells (Pendás et al, 2000). MMP13 is induced during invasion and metastasis of head and neck cancer, skin cancer, gastric cancer and breast cancer (Nielsen et al, 2001;Elnemr et al,2003;Luukkaa et al, 2006;Lederle et al, 2010). This study demonstrated that mRNA expression of LPHN3 and MMP13 is directly linked to tumor aggressiveness, since the common first route of spread for breast carcinoma is through the axillary lymph nodes.…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…For example, studies of mice lacking MMP13 have shown that it is essential for maintenance of angiogenesis and for tumor-cell invasion. In wildtype mice, MMP13 is induced in fibroblasts at the onset of tumor invasion, resulting in release of VEGF from the ECM (Lederle et al 2010).…”

Effects of selective MMP-13 inhibition in squamous cell carcinoma depend on estrogen

“…[16][17][18] Tumor progression is mediated by a crosstalk between tumor and stromal cells like fibroblasts, blood vessels and inflammatory cells that secrete growth factors, matrix components and proteases like MMPs.…”

“…[8][9][10][11] Expression of human collagenase-3 (hMMP-13) is associated with invasion and metastasis in a variety of malignant tumors [breast, squamous cell carcinomas (SCCs), HNSCCs and melanomas] [12][13][14][15] where it is found in tumor cells, but also in stromal cells. [16][17][18] Tumor progression is mediated by a crosstalk between tumor and stromal cells like fibroblasts, blood vessels and inflammatory cells that secrete growth factors, matrix components and proteases like MMPs. 19 As a consequence, in vivo models, mostly of murine background, are essential to analyze the complex interplay between tumor and stroma derived MMPs in cancer.…”

“…22 Previous experiments have shown a striking involvement of MMP-13 in the growth and invasion of in human and murine skin SCC. 16,23 The strong connection between MMP overexpression and tumor progression led to the development of MMP inhibitors (MMPI) as cancer therapeutics. However, clinical trials with broad-spectrum inhibitors failed due to the poor validation of adequate drug targets, the opposing roles of MMPs in cancer progression and the lack of inhibitor specificity.…”