MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: possible implications for the role of desmoplastic fibroblasts.
Expression of activated MMP-2 (72 kDa type IV collagenase) is highly associated with the malignant phenotype in adenocarcinomas, but predominant expression of the mRNA appears to be in stromal cells. MT1-MMP (membrane type 1-matrix metalloproteinase) is implicated in tumor-epithelial cell surface activation of latent pro-MMP-2, indicating a mechanism for tumor-stromal interaction in invasion. We determined the relative mRNA distribution of these MMPs in human ovarian tumors with a view to analyzing potential variations in the epithelial-mesenchymal interactions dictating ovarian tumor cell spread. In situ hybridization using 35S-labeled riboprobes was used to analyze 33 human ovarian tumors and mouse xenografts of human ovarian (DOV 13, SKOV3) and breast (MCF 7) tumor cell lines known to express MT1-MMP and MMP-2. MMP-2 mRNA was expressed in 31 of 33 and MT1-MMP mRNA was expressed in 29 of 33 tumor cases. MMP-2 mRNA was predominantly expressed in desmoplastic fibroblasts and in the subepithelial stroma. MT1-MMP mRNA showed some colocalization with MMP-2 in stromal cells. Neoplastic epithelial cell labeling for MT1-MMP mRNA was present in borderline and malignant tumors but not in benign tumors, and was invariably less than stromal labeling. Xenografts of DOV 13, SKOV 3, and MCF 7 cells showed some stromal localization of MMP-2 mRNA and weak labeling of DOV 13 cells. There was variable labeling for MT1-MMP mRNA in the neoplastic cells only. The colocalization of MT1-MMP and MMP-2 mRNAs in ovarian carcinoma stroma supports the view that MT1-MMP is closely associated with MMP-2 expression and function. It suggests that either additional mechanisms are involved in regulating MMP-2 activation at the tumor cell surface, or more intriguingly, that desmoplastic fibroblasts may be the primary mediators of extracellular matrix remodeling with respect to this system.
Afzal
S
S
Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Lalani
E N
EN
Poulsom
R
R
Stubbs
A
A
Rowlinson
G
G
Sato
H
H
Seiki
M
M
Stamp
G W
GW
D000199:Actins / Q000032:analysis / Q000378:metabolism; D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000232:Adenofibroma / Q000201:enzymology / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000473:pathology; D014407:Tumor Cells, Cultured
D000199:Actins; D014408:Biomarkers, Tumor; C507096:Mmp14 protein, mouse; D012333:RNA, Messenger; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14