Pathogenesis of ovarian cancer: clues from selected overexpressed genes

Abstract

Ovarian cancer is the most malignant gynecologic neoplasm. Although new chemotherapeutic agents have improved patients' 5-year survival rate, the overall mortality of ovarian cancer has remained largely unchanged in the past several decades. The main reason for the lack of success in effectively treating ovarian cancer is our limited understanding of its etiology and the very few molecular diagnostic markers and therapeutic targets known so far. Identification and characterization of ovarian cancer-associated genes are fundamental for unveiling the pathogenesis of its initiation and progression, especially the development of recurrent diseases. As there are a vast number of genes for which molecular genetic changes and aberrant gene expression have been reported in ovarian cancer, this review will only focus on summarizing those exemplified genes that have been demonstrated to have biological functions in promoting ovarian cancer development and potential clinical significance. The genes to be discussed include nuclear proteins (Notch3, HBXAP [Rsf-1], NAC1 and NFkappaB), cytoplasmic proteins (fatty acid synthase and apolipoprotein E) and cell surface/secretory proteins (mucin-4, mesothelin, claudin, HLA-G, kallikrein and folate receptor and osteopontin). Since the study of ovarian cancer-associated genes is complicated by several factors unique to ovarian cancer, we will also present our views on the limitations and challenges of current ovarian cancer research.

Figure 1. The main molecular genetic alterations in different types of ovarian epithelial carcinomas

The percentage of each genetic change is estimated based on several published studies. The volume of different histologic types of ovarian cancer reflects their approximate prevalence in ovarian cancer patients.

Figure 2. Possible functions of ovarian cancer-associated genes as discussed in this article

The overexpressed genes in ovarian cancer contribute to tumor progression by participating in several cellular processes including proliferation (cell-cycle progression), prevention of apoptosis, tumor invasion and metastasis, escape from anoikis (anchorage dependent growth), immune evasion, DNA damage repair and lipid synthesis. Several gene products, including HLA-G, mucin-4, FASN, folate receptor-α and osteopontin are secretory, and they may serve as serum biomarkers for cancer detection. Moreover, some upregulated proteins (Table 1) are potential therapeutic targets, as the reagents that inhibit their gene functions are available for current and future clinical applications. The arrow indicates a positive regulation and the block a negative regulation. The dashed lines denote nuclear translocation of the cytoplasmic or membrane proteins. FASN: Fatty acid synthase; HLA-G: Human leukocyte antigen-G; NICD3: Intracellular domain of Notch3.

Figure 3. Correlation of 11q13.5 amplification and overall survival in ovarian serous carcinoma patients

The 11q13.5 amplicon contains several genes including HBXAP (Rsf-1). Three independent studies apply the fluorescent in situ hybridization probes to detect the copy number of the 11q13.5 locus and demonstrate a significantly shorter overall survival in patients whose tumors harbor 11q13.5 amplification. The figures from the Vancouver General Hospital (BC, Canada) and the University of Münster (Münster, Germany) are courtesy of data from Dr Huntsman and Dr Staebler, respectively. FISH: Fluorescent in situ hybridization.