When overexpressed, or when an imbalance exists in respect to their tissue inhibitors (TIMPs), MMPs are implicated in a wide range of disease states, including arthritis, impaired wound healing and cancer invasion and metastasis. We have analysed MMP-1, -2, -3, -9, TIMP-1, and -2 mRNA expression levels in human ovarian carcinoma cell lines and ovarian tumors using a multigene specific, competition-based quantitative RT-PCR assay. Modulation experiments indicate that EGF family ligands such as TGF-alpha, and particularly serum deprivation alone, significantly upregulate MMP-1 (75 fold), MMP-9 (20 fold) and TIMP-2 mRNA expression (40 fold) in OVCAR-8 carcinoma cell line. A comparison of 10 ovarian Stage I Serous Borderline tumors with 10 Stage III/IV ovarian Serous Cystadenocarcinomas indicates expression of low copy numbers/cell of MMP-1 (1 to 5), intermediate numbers for MMP-2 (10-180), and very high copy numbers/cell (30 to 10,000) for TIMP-2. No clear distinction in pattern of mRNA expression was detected between the non-invasive and invasive carcinoma types. Ligands (growth factors, cytokines, etc.) and their receptors represent a major aspect of new product development within the biotechnology industry. Direct bench research in MMPS/TIMPs in extracellular matrix degradation, and its modulation by growth factors, provides knowledge of the scientific literature and the experts of the respective fields, and experience with their assay methodologies. Each of these are requirements to a rigorous, scientific approach to product regulation. Inhibitors of MMPs and several members of the EGF supergene family (for example, the ligands EGF, TGF-a, and HB-EGF) are currently products at the pre-IND or IND stage. Research in the Cellular Pathology Section of LCB, DCB, OTRR, CBER on growth factor modulation of MMP and TIMP expression will contribute directly to their development as pharmaceutical products, and will enhance the capacity of CBER to accomplish scientific-based regulation of cancer therapies based on the MMP/TIMP and EGF family of proteins.
