Perturbation of the Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Cascade in Ovarian Cancer: Overexpression of FLIPL and Deregulation of the Functional Receptors DR4 and DR5

Abstract

Purpose: Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancies. Due to advanced stage at diagnosis, most patients need systemic treatment in addition to surgery. Tumor necrosis factor (TNF)^related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with a promising toxicity profile and synergistic activity with chemotherapeutic agents. Experimental Design: We used an arrayed panel of epithelial ovarian cancer tissue to assess the protein expression of TRAIL and the clinically most relevant members of its pathway death receptors 4 and 5 (DR4 and DR5) and the long form of FLICE inhibitory protein (FLIP L ). Results: We could show that a majority (66.2%) of the tumor tissues displayed either reduced DR4/DR5 expression (20.6%), increased FLIP L expression (39.7%), or both (5.9%) as determined by immunohistochemistry. Furthermore, higher TRAIL expression in the surrounding connective tissue but not in the tumor cells is significantly (P < 0.05) linked with favorable overall survival in advanced-stage patients. Conclusions: Mechanisms to escape the immune surveillance mediated byTRAIL are developed by ovarian cancer cells in a high percentage. TRAIL expression in the ovarian cancer microenvironment has an effect on overall survival. These findings enhance our understanding of ovarian cancer pathology and might be helpful in guidingTRAIL-based therapy in future.Despite great clinical and research efforts, the etiology of ovarian cancer remains poorly understood. A majority (90%) of these tumors stem from ovarian surface epithelium, which is similar to the mesothelial lining of other abdominal organs. Beyond family history, the most important risk factors for ovarian cancer include early menarche, late menopause, nulliparity, and in contrast, the use of anovulatory drugs that reduces the risk. The epidemiologic observation that all factors that limit the number of ovulations over lifetime are protective against ovarian cancer resulted in the so-called incessant ovulation theory decades ago (1).Over the past several years, the molecular mechanisms behind the genetic predisposition for ovarian cancer have been elucidated. Germ line mutations in BRCA1 and BRCA2, the genes responsible for hereditary breast and ovarian cancer and in hMLH1 and hMSH2, responsible for hereditary nonpolyposis colon cancer, are also the basis for a majority of cases of familial ovarian cancer. Originally identified by positional cloning, all these genes were later shown to be involved in the maintenance of genome integrity, implying that DNA repair mechanisms are under considerable challenge in ovarian tissue. Induction of apoptosis plays a pivotal role in cellular homeostasis, and in this scenario, the impairment of any of its components may result in accumulation of genetic defects, preceding cancer development (2).Apoptosis is induced either by binding of ligands to specific death receptors on cell surface or by unspecific cellular stress, which promotes cytochrome c release from mi...

Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

“…Also, decreased DR5 expression was found in human tumors such as hepatoma 26 and ovarian cancer. 27 This indicates that downregulated DR5 may play a role in the pathogenesis of malignant tumors. In this study, we discovered that HBc significantly decreases DR5 mRNA and protein expression both in hepatoma cells and in murine hepatocytes.…”

An apoptotic molecular network identified by microarray: On the TRAIL to new insights in epithelial ovarian cancer

“…These results are consistent with those in the literature showing either Trail overexpression in early-stage EOC compared with advanced-stage EOC, or no association with disease stage. 21,22 However, at the RNA level, TRAIL was overexpressed in poorly differentiated (grade 2 and 3) tumors compared with welldifferentiated (grade 1) tumors. 23 This discordance between protein levels and RNA levels was reported previously in breast cancer 24 ; it also was reflected in our microarray analysis, in which grade 3 TOV tumors expressed higher levels of TRAIL than LMP tumors, and in another published microarray study in which TOV tumors were compared with normal ovarian surface epithelium cells.…”

Role and prognostic significance of tumor necrosis factor‐related apoptosis‐inducing ligand death receptor DR5 in nonsmall‐cell lung cancer and precursor lesions

“…19 In melanomas, high DR5 expression was associated with a longer disease-free survival in univariate analysis but was not an independent prognostic factor in multivariate analysis. 17 Studies of DR5 in colon cancer, 26,30 ovarian cancer 25 , and acute myelogenous leukemia 31 have not shown any association with prognosis. These findings are unexpected if death receptormediated proapoptotic signals are taking effect.…”