title: Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion.
abstract: BACKGROUND
  The actions of the extracellular-matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP-2, MMP-9, membrane type 1 (MT1)-MMP, tissue inhibitors of metalloproteinases (TIMPs) 1-3, and the presence of active gelatinases were investigated in endometrial carcinoma.
  
  
  METHODS
  Endometrial carcinomas were grouped according to histologic grade (Grades 1-3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty-nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP-2 (gelatinase A), MMP-9 (gelatinase B), MT1-MMP, and TIMPs 1-3. In situ hybridization was performed to localize MMP-2 and MMP-9 mRNA. The presence of active gelatinases was assessed using in situ zymography.
  
  
  RESULTS
  Epithelial tumor cells were the main site of MMP-2, MMP-9, and MT1-MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP-9 and MMP-2 but not MT1-MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase-9 and MT1-MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP-2 did not correlate with these factors. In addition, MT1-MMP was co-localized with MMP-2, supporting its role in the activation of proMMP-2. Tumor cells from all histologic grades stained intensely for TIMP-2 and TIMP-3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP-1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase-9 and MMP-2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues.
  
  
  CONCLUSIONS
  These data suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton, VIC, Australia. Lisa.Di.Nezza@med.monash.edu.au
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Di Nezza
authors.forename: Aileen
authors.initials: A
authors.lastname: Misajon
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Tom
authors.initials: T
authors.lastname: Jobling
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quinn
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Ostör
authors.forename: Guiying
authors.initials: G
authors.lastname: Nie
authors.forename: Alex
authors.initials: A
authors.lastname: Lopata
authors.forename: Lois A
authors.initials: LA
authors.lastname: Salamonsen
mesh_terms: D001706:Biopsy; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D004273:DNA, Neoplasm; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018093:Gelatinases / Q000096:biosynthesis* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis*
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9