title: The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation.
abstract: Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their alpha(1)-proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P = 0.003-0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P = 0.01-0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer.
authors.affiliation: Department of Clinical Chemistry, Helsinki University Central Hospital, Haartmaninkatu 2, Helsinki, FIN-00290, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Paju
authors.forename: T
authors.initials: T
authors.lastname: Sorsa
authors.forename: T
authors.initials: T
authors.lastname: Tervahartiala
authors.forename: E
authors.initials: E
authors.lastname: Koivunen
authors.forename: C
authors.initials: C
authors.lastname: Haglund
authors.forename: A
authors.initials: A
authors.lastname: Leminen
authors.forename: T
authors.initials: T
authors.lastname: Wahlström
authors.forename: T
authors.initials: T
authors.lastname: Salo
authors.forename: U H
authors.initials: UH
authors.lastname: Stenman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017364:Collagenases / Q000378:metabolism*; D018282:Cystadenocarcinoma, Mucinous / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D010048:Ovarian Cysts / Q000201:enzymology* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D014357:Trypsin; D014362:Trypsinogen / Q000032:analysis* / Q000378:metabolism
chemical_list: D004792:Enzyme Precursors; D007527:Isoenzymes; C064831:PRSS2 protein, human; D014362:Trypsinogen; D014357:Trypsin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020780:Matrix Metalloproteinase 9