Interference with the Complement System by Tumor Cell Membrane Type-1 Matrix Metalloproteinase Plays a Significant Role in Promoting Metastasis in Mice

Abstract

Neoplasms have developed strategies to protect themselves against the complement-mediated host immunity. Invasionand metastasis-promoting membrane type-1 (MT1) matrix metalloproteinase (MMP) is strongly associated with many metastatic cancer types. The relative importance of the individual functions of MT1-MMP in metastasis was, however, unknown. We have now determined that the expression of murine MT1-MMP in murine melanoma B16F1 cells strongly increased the number of metastatic loci in the lungs of syngeneic C57BL/6 mice. In contrast, MT1-MMP did not affect the number of metastatic loci in complement-deficient C57BL/6-C3 À/À mice. Our results indicated, for the first time, that the anticomplement activity of MT1-MMP played a significant role in promoting metastasis in vivo and determined the relative importance of the anticomplement activity in the total metastatic effect of this multifunctional proteolytic enzyme. We believe that our results shed additional light on the functions of MT1-MMP in cancer and clearly make this protease a promising drug target in metastatic malignancies.

Non-destructive and Selective Imaging of the Functionally Active, Pro-invasive Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Enzyme in Cancer Cells

“…Mock-transfected B16F1 cells (B16F1-mock cells) were employed as a control. As demonstrated earlier by us and others (59), the MT1-MMP 3G4 antibody efficiently crossreacted with the murine proteinase. Immunostaining using the MT1-MMP 3G4 antibody confirmed high levels of MT1-MMP in B16F1-mMT1 cells.…”

“…8B, long exposure). Based on our previous results (59), these data can be easily explained by the presence of the TIMP-2-free proteinase in B16F1-mMT1 cells. In these MT1-MMP-overexpressing cells, the levels of the proteinase exceed the available amounts of TIMP-2.…”

“…HT1080 cells with shRNA transcriptional silencing of MT1-MMP (HT-shMT1 cells) were isolated and characterized earlier (58). B16F1 cells stably transfected with the empty pcDNA3-zeo vector (B16F1-mock cells) or the pcDNA3-zeo plasmid encoding the murine full-length MT1-MMP (B16F1-mMT1) were also generated and described earlier (59).…”

Dual role of complement in tumour growth and metastasis (Review)

“…In fact, by design of the mouse models that demonstrate the relevance of downregulated CD55 or CD59 in decreasing tumour burden, these are metastatic either by route of administration of manipulated tumour cells (58) or by the time of observation (s.c., 6 weeks) (52). Thus, it appears that adjuvant support of C5a may hold promise in limiting metastasis, thereby providing a unifying hypothesis as to the reason for significantly less tumour burden in wildtype compared to C3 deficient mice in a metastasising melanoma model (57), while the blockade of C5a leads to a reduced tumour burden in neoplastic growth models. It is unclear at present to which extent the C5a receptors, C5aR and C5L2 (a decoy receptor of C5aR with anti-inflammatory properties; ref.…”

“…Similarly, matrix metalloproteinase-1 cleaves complement C3 and protects tumour cells from injury. Its prometastatic activity is directly related to the ability of matrix metalloproteinase-1 to cleave C3, as seen from in vivo models using matrix metalloproteinase-1 transfected tumour cells, C3-deficient mice, and their controls (57). Tumour-associated complement activation may significantly enhance tumour growth by suppressing the antitumour cellular immune response (20).…”