Leber, Thomas Matthias; (1998) Regulation of MMP-9 in human ovarian cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Matrix metalloproteases (MMPs) are a family of structurally and functionally related endopeptidases. They have a zinc ion at their active site and are released as inactive pro-forms. Activation enables MMPs to degrade components of the extracellular matrix and this been associated with tumour growth and metastasis. The aim of this thesis was to establish the pattern of MMPs and tissue inhibitor of metalloproteinases (TIMPs) present in human ovarian cancer and to investigate further one MMP, MMP-9. MMP/TIMP gene expression was assessed by RT-PCR in biopsies of normal, benign and malignant human ovary and compared to ovarian cancer cell lines and xenograft models of human ovarian cancer. Expression of MMP-2, -11, MT-1-MMP, TIMP-1, -2 and -3 was detectable in all tissue samples. MMP-1, -10 and MT-2-MMP were rarely detectable and MMP-3, -7, -9, -13 and MT-3-MMP were variably expressed. MMP/TIMP expression in the malignant biopsies was similar to that in ovarian cancer cell lines and xenograft models of human ovarian cancer. MMP-9 production was further investigated in an in vitro model of tumour cell macrophage interaction. In human ovarian cancer MMP-9 localises to infiltrating macrophages but little is known of its regulation. Co-culture of ovarian cancer cells (PEO1) and a monocytic cell line (THP-1) led to production of 92kDa proMMP-9. PEO1 conditioned medium (CM) also stimulated THP-1 cells or isolated peripheral blood monocytes to produce proMMP-9. Expression of TIMP-1, however, remained unaffected. The metalloprotease stimulating factor (MMPSF) present in CM was not TNF-a, but acted in a synergistic fashion with autocrine monocyte-derived TNF-a to stimulate release of monocytic proMMP-9. MMPSF was further characterised. In all experiments only proMMP-9 was released. Cell extracts of THP-1 cells contained a 92 and 85kDa form of MMP-9. N-terminal sequencing revealed that both proteins contained the full pro-peptide and were therefore proteolytically inactive pro-forms of MMP-9.

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