MMP inhibition blocks fibroblast-dependent skin cancer invasion, reduces vascularization and alters VEGF-A and PDGF-BB expression.
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.
Woenne
Eva C
EC
Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, D-52074 Aachen, Germany.
Lederle
Wiltrud
W
Zwick
Stefan
S
Palmowski
Moritz
M
Krell
Hans
H
Semmler
Wolfhard
W
Mueller
Margareta M
MM
Kiessling
Fabian
F
D000818:Animals; D000077214:Becaplermin; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D053505:Matrix Metalloproteinases, Secreted / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009930:Organic Chemicals / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
D009930:Organic Chemicals; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C453902:Ro 28-2653; D019715:Tissue Inhibitor of Metalloproteinase-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C113282:prinomastat; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077214:Becaplermin; D003094:Collagen; D053505:Matrix Metalloproteinases, Secreted