Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells.
Reversible modulation of cell-cell adhesion, cell-matrix adhesion, and proteolytic activity plays a critical role in remodeling of the neoplastic ovarian epithelium during metastasis, implicating cadherins, integrins, and proteinases in i.p. metastatic dissemination of epithelial ovarian carcinoma (EOC). Aberrant epithelial differentiation is an early event in ovarian carcinogenesis; thus, in contrast to most carcinomas that lose E-cadherin expression with progression, E-cadherin is abundant in primary EOC. Metastasizing EOCs engage in integrin-mediated adhesion to submesothelial interstitial collagens and express matrix metalloproteinases (MMP) that facilitate collagen invasion, thereby anchoring secondary lesions in the submesothelial matrix. As metalloproteinases have also been implicated in E-cadherin ectodomain shedding, the current study was undertaken to model the effects of matrix-induced integrin clustering on proteinase-catalyzed E-cadherin ectodomain shedding. Aggregation of collagen-binding integrins induced shedding of an 80-kDa E-cadherin ectodomain [soluble E-cadherin (sE-cad)] in a MMP- and Src kinase-dependent manner, and sE-cad was prevalent in ascites from ovarian cancer patients. Expression of MMP-9 was elevated by integrin aggregation, integrin-mediated ectodomain shedding was inhibited by a MMP-9 function blocking antibody, and incubation of cells with exogenous MMP-9 catalyzed E-cadherin ectodomain shedding. In contrast to other tumors wherein sE-cad is released into the circulation, EOC tumors maintain direct contact with sE-cad-rich ascites at high concentration, and incubation of EOC cells with physiologically relevant concentrations of recombinant sE-cad disrupted adherens junctions. These data support a novel mechanism for posttranslational modification of E-cadherin function via MMP-9 induction initiated by cell-matrix contact and suggest a mechanism for promotion of EOC metastatic dissemination.
Symowicz
Jaime
J
Departments of Cell and Molecular Biology and Pathology, Northwestern University Feinberg Medical School, Chicago, IL, USA.
Adley
Brian P
BP
Gleason
Kara J
KJ
Johnson
Jeffrey J
JJ
Ghosh
Supurna
S
Fishman
David A
DA
Hudson
Laurie G
LG
Stack
M Sharon
MS
D022005:Adherens Junctions / Q000378:metabolism / Q000502:physiology; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D021982:Cell-Matrix Junctions / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D014407:Tumor Cells, Cultured
D015820:Cadherins; D016023:Integrins; D003094:Collagen; D020780:Matrix Metalloproteinase 9