Tumor Necrosis Factor-α-Induced Matrix Proteolytic Enzyme Production and Basement Membrane Remodeling by Human Ovarian Surface Epithelial Cells

Abstract

The majority of cancer is of surface/cyst epithelial origin. The ovarian surface epithelial cells are organized by a sheet of basement membrane composed mainly of collagen IV and laminin, and it is believed that the basement membrane greatly influences the physiological properties of ovarian surface epithelial cells. Previous studies in our laboratories indicated that loss of the basement membrane, an obligated step in ovulation, is also a critical step during the morphological transformation and tumor initiation of the ovarian surface epithelium. It is speculated that the loss of basement membrane in ovarian surface epithelial transformation may have similar biological mechanism to the loss of surface epithelial basement membrane in ovulation. However, the mechanisms involved in the ovarian surface epithelial basement membrane removal during ovulation are still not completely understood. In the current study, cultured human ovarian surface epithelial (HOSE) cells were examined for their abilities to produce matrix hydrolyzing enzymes and degrade basement membrane in response to a number of potential local mediators in ovulation. Among the candidate-stimulating factors tested, tumor necrosis factor (TNF)-␣ and IL-1␤ (to a lesser extent) were found to drastically increase urokinase type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 activities secreted from HOSE cells. MMP-2, the other major HOSE cellsecreted gelatinase, is constitutively produced but not regulated. As demonstrated by immunofluorenscence staining and Western blot analysis, TNF-␣ treatment caused the degradation and structural reorganization of collagen IV and laminin secreted and deposited by HOSE cells in culture. Amiloride, an uPA inhibitor, not only inhibited the activity of uPA but was also able to suppress TNF-␣-stimulated MMP-9 activity and prevented the TNF-␣-stimulated remodeling of the basement membrane extracellular matrix, suggesting the contribution of uPA-mediated proteolytic cascade in this process. This study implicates the potential roles of TNF-␣, uPA, and MMP-9 in ovarian surface epithelial basement membrane degradation and remodeling, which are processes during ovulation and may contribute to epithelial transformation. The findings may underscore the importance of TNF-␣, uPA, and MMP-9 in ovarian surface epithelial basement membrane remodeling and may provide a molecular mechanism linking ovulation and ovarian cancer risk.

Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β

“…Expression of MMP-9 is regulated at transcription level and can be induced by classic mediators such as TNF-α (Yang et al, 2004), TGF-β (Rundhaug et al, 1997), EGF (Menashi et al, 2003) or HGF (Park et al, 2003). In our experiments, induction of MMP-9 did not require cell-cell contacts or viability of CA1a cells, indicating that it depends on one or more soluble factors already present in naive CA1a cells.…”

Loss of TNF-α-regulated COX-2 expression in ovarian cancer cells

“…In ovarian cancer etiology, TNF-a-mediated inflammation has been proposed to contribute to cancer risk (Ness and Cottreau, 2000;Yang et al, 2004). Consistent with this idea, TNF-a is able to stimulate expression of COX-2 in nontumorigenic ovarian surface epithelial cells.…”

Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

“…The ovarian cancer cell line BR was established as described previously (Wang et al, 1998). An immortalized human ovarian surface epithelial cell line (IOSE-80PC), originally from Dr Andrew K Godwin (Fox Chase Cancer Center, Philadelphia, PA, USA) (Yang et al, 2004), was provided by Dr Peter CK Leung (British Columbia Children's and Women's Hospital, Vancouver, BC, Canada) (Choi et al, 2006). Another human ovarian surface epithelial (HOSE) cell line was provided by Dr SW Tsao (University of Hong Kong, Hong Kong) (Chung et al, 2005).…”