Ovarian Cancer Cell Detachment and Multicellular Aggregate Formation Are Regulated by Membrane Type 1 Matrix Metalloproteinase: A Potential Role in I.p. Metastatic Dissemination

Abstract

An early event in the metastasis of epithelial ovarian carcinoma is shedding of cells from the primary tumor into the peritoneal cavity followed by diffuse i.p. seeding of secondary lesions. Anchorage-independent metastatic cells are present as both single cells and multicellular aggregates (MCA), the latter of which adhere to and disaggregate on human mesothelial cell monolayers, subsequently forming invasive foci. Although this unique metastatic mechanism presents a distinct set of therapeutic challenges, factors that regulate MCA formation and dissemination have not been extensively evaluated. Proteolytic activity is important at multiple stages in i.p. metastasis, catalyzing migration through the mesothelial monolayer and invasion of the collagen-rich submesothelial matrix to anchor secondary lesions, and acquisition of membrane type 1 matrix metalloproteinase (MT1-MMP; MMP-14) expression promotes a collagen-invasive phenotype in ovarian carcinoma. MT1-MMP is regulated posttranslationally through multiple mechanisms including phosphorylation of its cytoplasmic tail, and the current data using ovarian cancer cells expressing wildtype, phosphomimetic (T567E-MT1-MMP), and phosphodefective (T567A-MT1-MMP) MT1-MMP show that MT1-MMP promotes MCA formation. Confluent T567E-MT1-MMPexpressing cells exhibit rapid detachment kinetics, spontaneous release as cell-cell adherent sheets concomitant with MT1-MMP-catalyzed A 3 integrin ectodomain shedding, and robust MCA formation. Expansive growth within threedimensional collagen gels is also MT1-MMP dependent, with T567E-MT1-MMP-expressing cells exhibiting multiple collagen invasive foci. Analysis of human ovarian tumors shows elevated MT1-MMP in metastases relative to paired primary tumors. These data suggest that MT1-MMP activity may be key to ovarian carcinoma metastatic success by promoting both formation and dissemination of MCAs. [Cancer Res 2009;69(17): 7121-9]

Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

“…Indeed less "classical" inflammatory mediators such as hypoxia, HIF-2b, Wnt family members, or epigenetic changes in DNA methylation may well serve as dominant players in the control of MT1-MMP expression or activity in RA (64)(65)(66)(67)(68)(69). Nevertheless, given the expression of MT1-MMP within RA synoviocytes at sites of tissue damage in vivo, its pathophysiologically relevant functional properties, and the recent development of MT1-MMP-specific inhibitors (70), the proteinase could serve as an important target for therapeutic intervention.…”

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

“…Implantation of spheroids on the peritoneum involves interactions between cancer cells and the mesothelium. Adhesion of ovarian cancer cells to the mesothelial layer is facilitated by the expression of matrix metalloproteinase such as MMP-2 and MMP-9, and by ibronectin and vitronectin as well as their integrin receptors [67][68][69]. Once tumor cells have atached to the peritoneal surface, they gain access to the submesothelial environment by exerting force on the mesothelial lining, driving migration and clearance of the mesothelial cells [70].…”

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

“…Laminin-5 and Collagen Type I Attenuate MT1-MMP-induced Cellular Aggregation-Prior studies have demonstrated that MT1-MMP can affect cellular behavior by cleaving integrins from the cell surface (47,51,52). Therefore, we induced MT1-MMP in SCC25 cells and used FACS analysis to examine subsequent effects on the relative cell surface levels of ␤1-, ␣2-, and ␣3-integrins.…”