MMP Inhibition Blocks Fibroblast-dependent Skin Cancer Invasion, Reduces Vascularization and Alters VEGF-A and PDGF-BB Expression

• Published in: Anticancer research Vol. 30; no. 3; pp. 703 - 711
• Main Authors: WOENNE, Eva C, LEDERLE, Wiltrud, ZWICK, Stefan, PALMOWSKI, Moritz, KRELL, Hans, SEMMLER, Wolfhard, MUELLER, Margareta M, KIESSLING, Fabian
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.03.2010
• Subjects: Animals; Biological and medical sciences; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Collagen - metabolism; Dermatology; Fibroblasts - enzymology; Fibroblasts - pathology; Humans; Matrix Metalloproteinases, Secreted - antagonists & inhibitors; Matrix Metalloproteinases, Secreted - biosynthesis; Matrix Metalloproteinases, Secreted - metabolism; Medical sciences; Mice; Mice, Nude; Neoplasm Invasiveness; Organic Chemicals - pharmacology; Piperazines - pharmacology; Platelet-Derived Growth Factor - biosynthesis; Proto-Oncogene Proteins c-sis; Pyrimidines - pharmacology; Skin Neoplasms - blood supply; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - biosynthesis; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vascular Endothelial Growth Factor A - biosynthesis; Xenograft Model Antitumor Assays; Skin disease; Enzyme; Cytokine; Metalloendopeptidases; Malignant tumor; Metastasis; imaging; Invasion; Skin cancer; Vascularization; MMP inhibition; Peptidases; Angiogenesis; Cancerology; Vascular endothelium growth factor; Hydrolases; Medical imagery; Inhibitor; Skin; Neovascularization; Fibroblast; Platelet derived growth factor; Cancer
• ISSN: 0250-7005; 1791-7530

Tumor invasion requires intense interactions with stromal cells and a profound extracellular matrix remodelling by matrix metalloproteinases (MMPs). Here, we assessed the specific contribution of fibroblasts to tumor invasion, MMPs, tissue inhibitors of MMPs and angiogenesis-related cytokine expression in organotypic cultures of highly malignant HaCaT-ras A-5RT3 cells, with and without MMP inhibition. Collagen degradation, the hallmark of tumor invasion, was dependent on fibroblasts and active MMP-2. Additionally, MMP blockade down-regulated VEGF-A and up-regulated PDGF-BB. These results were paralleled in xenotransplants in vivo, demonstrating strong inhibitory effects of MMP blockade on tumor invasion and vascularization, as shown by the almost complete absence of VEGF-A and MMP-14 and by the decrease in relative blood volume. MMP blockade also increased the fraction of mature vessels, as demonstrated by an increased mean tumor vessel diameter and a higher ratio of Ng2-positive vessels. Thus, this study highlights the importance of targeting the tumor stroma to defeat cancer.