Elsevier

Human Pathology

Volume 29, Issue 2, February 1998, Pages 155-165
Human Pathology

Original contribution
MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: Possible implications for the role of desmoplastic fibroblasts

https://doi.org/10.1016/S0046-8177(98)90226-XGet rights and content

Abstract

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 proMMP-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 (MCF7) 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 border-line 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.

References (53)

  • G Murphy et al.

    The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity

    Biochemistry

    (1991)
  • GI Goldberg et al.

    Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2

  • LA Liotta et al.

    Tumor invasion and metastasis: An imbalance of positive and negative regulation

    Cancer Res

    (1991)
  • K Tryggvason et al.

    Type IV collagenases in invasive tumors

    Breast Cancer Res Treat

    (1993)
  • PD Brown et al.

    Association between expression of activated 72-kilodalton gelatinase and tumor spread in non small-cell lung carcinoma

    J Natl Cancer Inst

    (1993)
  • B Davies et al.

    Activity of type IV collagenases in benign and malignant breast disease

    Br J Cancer

    (1993)
  • MR Emmert Buck et al.

    Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples

    Am J Pathol

    (1994)
  • R Poulsom et al.

    Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia

    Am J Pathol

    (1992)
  • R Poulsom et al.

    Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin

    J Clin Pathol

    (1993)
  • C Pyke et al.

    Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization

    Cancer Res

    (1992)
  • S Afzal et al.

    Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression and synthetic matrix metalloproteinase-2 inhibitor binding in ovarian carcinomas and tumour cell lines

    Lab Invest

    (1996)
  • E Campo et al.

    Evaluation of basement membrane components and the 72 kDa type IV collagenase in serous tumors of the ovary

    Am J Surg Pathol

    (1992)
  • WG Stetler Stevenson et al.

    Extracellular matrix 6: Role of matrix metalloproteinases in tumor invasion and metastasis

    FASEB J

    (1993)
  • JM Lewalle et al.

    Plasma membrane-dependent activation of gelatinase A in human vascular endothelial cells

    J Cell Physiol

    (1995)
  • HP Emonard et al.

    Tumor cell surface-associated binding site for the M(r) 72,000 type TV collagenase

    Cancer Res

    (1992)
  • PC Brooks et al.

    Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin

    J Clin Invest

    (1995)
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    Supported by a grant from the Association for International Cancer Research.

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