EGF-Receptor Regulation of Matrix Metalloproteinases in Epithelial Ovarian Carcinoma

Abstract

Ovarian carcinoma is most frequently detected when disease has already disseminated intraabdominally, resulting in a 5-year survival rate of less than 20% owing to complications of metastasis. Peritoneal ascites is often present, establishing a unique microenvironmental niche comprised of tumor and inflammatory cells, along with a wide range of bioactive soluble factors, several of which stimulate the EGF-receptor (EGFR). Elevated EGFR is associated with less favorable disease outcome in ovarian cancer, related in part to EGFR activation of signaling cascades that lead to enhanced matrix metalloproteinase expression and/or function. The available data suggest that modulating the expression or activity of the EGFR and/or matrix metalloproteinases offers opportunity for targeted intervention in patients with metastatic disease. KeywordsEGF-receptor; invasion; metastasis; MMP-9; MT1-MMP/MMP-14; ovarian carcinoma Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in 15,520 deaths in the USA in 2008 [201]. When disease is confined to the ovary, 5-year survival is greater than 90%. Unfortunately, the majority of women with EOC are diagnosed with already disseminated intra-abdominal disease and have a low 5-year survival rate of less than 20%. Thus, while early detection is a pressing clinical problem, analysis of factors that promote metastatic dissemination can ultimately improve the survival of women with ovarian cancer. Ovarian tumor microenvironmentA dualistic model for ovarian tumorigenesis has been proposed that is characterized by specific genetic alterations and unique molecular signatures [1][2][3]. In this classification system, lowgrade carcinomas are often confined to the ovary, arise from a recognized precursor lesion, †Author (Figure 1) [9][10][11]. These shed tumor cells may also block peritoneal lymphatics [12], contributing to the accumulation of peritoneal ascites, which can further facilitate metastatic implantation. Single cells and MCAs adhere to peritoneal mesothelium, where upon adhesive interactions and localized proteolysis enable anchoring of proliferative secondary lesions [9,10]. An exception is found in atypical proliferative serous tumors or micropapillary proliferative serous tumors (grouped as 'borderline' or 'low malignant potential'), the prognosis of which requires evaluation of peritoneal implants that often accompany these tumors. While patients with 'noninvasive implants' have a 10-year survival of practically 100%, a 34% mortality within 7 years is observed for those patients with invasive implants [12].An unique microenvironmental niche is thereby established in the peritoneal cavity, comprised of tumor cells, inflammatory cells and a plethora of soluble factors secreted by -or in response to -tumor cells, including growth factors, inflammatory mediators, bioactive lipids and proteolytic enzymes [13][14][15][16][17][18][19][20]. In addition, products of matrix invasion or partially resolved fibrosis, as well as shed...

Increased DNA methyltransferase activity and DNA methylation following epidermal growth factor stimulation in ovarian cancer cells

“…This work may have clinical significance given that the ovarian tumor environment contains numerous EGFR activators 2 and approximately 35% of all ovarian cancer tumors are positive for activated EGFR. 3,4 Using an in vitro paradigm of EGF exposure of OVCA 433 cells, we found that acute and long-term EGFR activation increases DNMT activity.…”

“…1 Ovarian cancer progression is characterized by the accumulation of ascites in which there are several activators of epidermal growth factor receptor (EGFR) including heparin-binding EGF (HB-EGF), endothelin-1 (ET-1) and lysophosphatidic acid (LPA). 2 The presence of these activators in patient ascites suggests that the tumor microenvironment is under chronic EGFR activation and may account for the observation that approximately 35% of all ovarian cancer tumors are positive for activated EGFR (tyrosine phosphorylated EGFR). 3,4 Overexpression of EGFR, and its ligands, has been detected in ovarian tumors and correlates with poor prognosis.…”

“…Activation of EGFR stimulates numerous downstream signaling cascades including Ras and Extracellular-signal Regulated Kinase (ERK)/Mitogen Activated Protein Kinase (MAPK), which are associated with cell growth, proliferation, survival, angiogenesis, cell migration, cell-cell/cell-matrix interaction and tumor metastasis. 2,3,7,8 Activation of EGFR is also reported to induce an epithelial to mesenchymal transition (EMT). 2,3,9,10 EMT is important in ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation.…”

“…2,3,7,8 Activation of EGFR is also reported to induce an epithelial to mesenchymal transition (EMT). 2,3,9,10 EMT is important in ovarian cancer progression is correlated with accumulation of aberrant CpG island methylation. in ovarian cancer, ascites fluid contains numerous epidermal growth factor receptor (EGfr) activators, which could result in a tumor microenvironment of constant EGfr activation.…”

Revisiting the Role of Antiandrogen Strategies in Ovarian Cancer

“…The latter leads to the stimulation of numerous downstream signaling cascades associated with cell growth and survival, angiogenesis, and tumor metastasis. In EOC, EGFR expression has been reported to be in the range of 10%-70% (with an average of 50%) [44] and EGFR amplification has been reported to be in the range of 1%-6% of cases [45]. Indeed, studies on prostate cancer cells suggest that there is crosstalk between AR and EGFR [46].…”