MMPs in Ovarian Cancer as Therapeutic Targets
ABSTRACT In the United States, about 22,000 women will be diagnosed with ovarian cancer in 2011, and an estimated 14,000 patients will succumb to the disease . Surgery and chemotherapy present the main treatment modalities, but despite the development of novel therapies, the overall 5 years survival for ovarian cancer patients with advanced disease at diagnosis remains at only about 30%. Novel therapeutic strategies are needed to prolong survival and achieve greater cure rates. Matrix metalloproteinases (MMPs) are frequently expressed in ovarian cancer, and play an important role in the metastatic process. MMPs mediate degradation of the basement membrane as a crucial step in epithelial transformation, ovarian tumorigenesis and intraperitoneal metastasis . Various preclinical and clinical studies have demonstrated that MMPs might provide a suitable therapeutic target. This review summarizes important observations regarding the expression of MMPs in ovarian cancer, their biological role, and data from clinical trials targeting MMPs in ovarian cancer patients.
- SourceAvailable from: Xuan Bich Trinh[Show abstract] [Hide abstract]
ABSTRACT: Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G 1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis.Cell cycle (Georgetown, Tex.) 02/2013; 12(6). DOI:10.4161/cc.23963 · 4.57 Impact Factor
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ABSTRACT: Modern cancer research requires physiological, three-dimensional (3D) cell culture platforms, wherein the physical and chemical characteristics of the extracellular matrix (ECM) can be modified. In this study, gelatine methacrylamide-based hydrogels (GelMA) were characterised and established as in vitro and in vivo spheroid-based models for ovarian cancer, reflecting the advanced disease stage of patients, with accumulation of multicellular spheroids in the tumour fluid (ascites). Polymer concentration (2.5-7% w/v) strongly influenced hydrogel stiffness (0.5 ± 0.2 kPa – 9.0 ± 1.8 kPa) but had little effect on solute diffusion. The diffusion coefficient of 70 kDa FITC-labelled dextran in 7% GelMA-based hydrogels was only 2.3-times slower compared to water. Hydrogels of medium concentration (5% w/v GelMA) and stiffness (3.4 kPa) allowed spheroid formation and high proliferation and metabolic rates. The inhibition of matrix metalloproteinases and consequently ECM degradability reduced spheroid formation and proliferation rates. The incorporation of the ECM components laminin-411 and hyaluronic acid further stimulated spheroid growth within GelMA-based hydrogels. The feasibility of pre-cultured GelMA-based hydrogels as spheroid carriers within an ovarian cancer animal model was proven and led to tumour development and metastasis. These tumours were sensitive to treatment with the anti-cancer drug paclitaxel, but not the integrin antagonist ATN-161. While paclitaxel and its combination with ATN-161 resulted in a treatment response of 33-37.8%, ATN-161 alone had no effect on tumour growth and peritoneal spread. The semi-synthetic biomaterial GelMA combines relevant natural cues with tunable properties providing an alternative, bioengineered 3D cancer cell culture in vitro and in vivo model system.Acta Biomaterialia 06/2014; 10(6):2551–2562. DOI:10.1016/j.actbio.2014.02.035 · 6.03 Impact Factor
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ABSTRACT: Gynecorelogic cancers like ovarian, cervical, and endometrial cancers are among the major threats to modern life, especially to female health. Like some other types of cancers, all of these gynecological cancers have found to be associated with the developmental stage epithelial to mesenchymal transition (EMT). More specifically, the aberrant expression of major EMT markers, such as lower expressions of E-cadherin and alpha-catenin, and overexpressions of N-cadherin, beta-catenin, vimentin, and matrix metalloproteinases, have been reported in ovarian, cervical, and endometrial cancers. The transcription factors, such as Twist, Snail, Slug, and Zeb, which regulate these EMT mediators, are also reported to be overexpressed in gynecological cancers. In addition to the over/lower expression, the promoter methylation of some of these genes has been identified too. In the era of target-specific cancer therapeutics, some promising studies showed that targeting EMT markers might be an interesting and successful tool in future cancer therapy. In this study, we have reviewed the recent development in the research on the association of EMT markers with three major gynecological cancers in the perspectives of carcinogenesis and therapeutics.Tumor Biology 08/2014; 35(10). DOI:10.1007/s13277-014-2537-1 · 3.61 Impact Factor