Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation.
Expression of matrix metalloproteinases (MMPs) and their activation in tumor cells, as well as tumor surrounding stromal cells have been implicated in tumor cell invasion and metastasis. By means of a syngeneic tumor model for either experimental or spontaneous metastases, the differential expression of MMPs and tissue inhibitors of MMPs (TIMPs) in relation to the microenvironment and the way of metastasis induction was characterized. In vitro characterization revealed that increased levels of secreted MMP-2, MMP-9, and TIMP-1 were only detectable in the most aggressive cell line, B16G3.12BM2. Remarkably, active MMP-2 was restricted to this cell line, whereas TIMP-2 and membrane type (MT) 1-MMP expression was comparable in all three of the spontaneously metastasizing melanoma cell lines investigated. In vivo analysis demonstrated that MMP-2, MMP-9, and MT1-MMP were predominantly expressed at the tumor-stroma border of s.c. tumors. Furthermore, functional active MMP-2 was restricted to this invasive front. In spontaneous lymph node or lung metastases, however, MMP-9 was expressed both in the center and the periphery of tumors; these areas were largely negative for MMP-2 and MT1-MMP. Notably, tumor cells of experimental lung metastases did not express MMP-9 at all. These results indicate that expression of MMPs in melanoma metastases is not only influenced by their localization but also the nature of tumor induction, suggesting that individual MMPs serve specific roles during the different stages of metastasis formation.
Hofmann
Uta B
UB
Department of Dermatology, Julius Maximilian's University, Würzburg, Germany. hofmann.ul@klinik.uni-wuerzburg.de
Eggert
Andreas A O
AA
Blass
Katharina
K
Bröcker
Eva-B
EB
Becker
Jürgen C
JC
D000818:Animals; D005260:Female; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary; D008207:Lymphatic Metastasis; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000473:pathology / Q000556:secondary*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis
C507096:Mmp14 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14