MMP-3於卵巢癌細胞株SKOV-3之表現以及對於侵襲與增殖的影響

Abstract

Epithelial ovarian cancer (EOC) is one of the major cancers in the female. The most common and most suffering condition in terminal stage is intra-abdominal carcinomatosis. Intraperitoneal tumor spreading involves the interaction between the tumor cells, peritoneum, and the extracellular matrix (ECM) around them. Therefore, stromal therapy might be an option of future strategy for the treatment of EOC. Matrix metalloproteinase (MMP) play important roles in these ECM reactions. Animal models had shown that many kinds of MMP facilitate cancer invasion and metastasis, and several kinds of MMP are regarded as treatment targets in cancer. However, most of the MMP-inhibition clinical trials failed to demonstrate survival benefit in cancer patients and some of the clinical trials were terminated early because of excessive side effect or even worse survival. The failure of MMP-inhibition clinical trials is due to the inadequate understanding of the complicated functions and multiple roles of MMP. To develop an effective stromal therapy to inhibit tumor progression, it is important to understand the role of various MMP in various kinds of cancer in various stages. MMP-3 (stromelysin-1) is rarely studied in EOC, and its role on EOC is not clear. The current study investigated the expression of MMP-3 in human ovarian carcinoma cell line SKOV-3, and its influence on the invasion and proliferation of SKOV-3 cells. The results of the current study revealed that while cultured alone, ovarian cancer SKOV-3 cells itself express small amount of MMP-3, but MMP-3 couldn’t be definitely detected in the supernatant in the culture dish. While cultured alone, fibroblast WS-1 cells released small amount of MMP-3. When the two kinds of cells were co-cultured together, ovarian cancer SKOV-3 cells promoted their surrounding fibroblast WS-1 to release much more MMP-3 than when cultured alone individually. The activated form of MMP-3 was located extracellularly, and its quantity had a grossly positive correlation with the quantity of total MMP-3 released extracellularly. In the SKOV-3 tumor model in nude mice, the tumor of more advanced stage had more prominent MMP-3 stain in the nucleus but less extra-nuclear MMP-3 stain. Co-culturing with fibroblast WS-1 cells significantly enhanced the invasive potential of the ovarian cancer SKOV-3 cells. For the ovarian cancer SKOV-3 cells cultured alone, the addition of either recombinant human pro-MMP-3, MMP-3 inhibitor-1, or recombinant human TIMP-3 (tissue inhibitor of matrix proteinase-3) enhanced the invasive potential and cell proliferation. When the ovarian cancer SKOV-3 cells were co-cultured with fibroblast WS-1, the addition of either trace MMP-3 inhibitor-1, trace TIMP-3 or excessive pro-MMP-3 inhibited the invasive potential of the SKOV-3 cells. Based on the current study, it implies that the stromal cells surrounding the cancer cells exert significant influence on the proliferation and invasion of the cancer cells. Such influence partly functions via the MMP/TIMP system. However, the function of the MMP/TIMP system is complicated and difficult to predict. The feasibility of a stromal therapy strategy requires thorough deliberation if the strategy is to be exerted via manipulating the MMP/TIMP system.