Therapeutic strategies for targeting the ovarian tumor stroma

Abstract

Epithelial ovarian cancer is the most lethal type of gynecologic malignancy. Sixty percent of women who are diagnosed with ovarian cancer present with advanced-stage disease that involves the peritoneal cavity and these patients have a 5-year survival rate of less than 30%. For more than two decades, tumor-debulking surgery followed by platinum-taxane combination chemotherapy has remained the conventional first-line treatment of ovarian cancer. Although the initial response rate is 70%-80%, most patients with advanced-stage ovarian cancer eventually relapse and succumb to recurrent chemoresistant disease. A number of molecular aberrations that drive tumor progression have been identified in ovarian cancer cells and intensive efforts have focused on developing therapeutic agents that target these aberrations. However, increasing evidence indicates that reciprocal interactions between tumor cells and various types of stromal cells also play important roles in driving ovarian tumor progression and that these stromal cells represent attractive therapeutic targets. Unlike tumor cells, stromal cells within the tumor microenvironment are in general genetically stable and are therefore less likely to become resistant to therapy. This concise review discusses the biological significance of the cross-talk between ovarian cancer cells and three major types of stromal cells (endothelial cells, fibroblasts, macrophages) and the development of new-generation therapies that target the ovarian tumor microenvironment.

Keywords: Ovarian cancer, Tumor stroma, Endothelial cells, Fibroblasts, Macrophages, Targeted therapy

Core tip: Despite advances in clinical management, advanced-stage ovarian cancer is still rarely cured by conventional chemotherapy. Substantial efforts have been directed to developing new therapies that target ovarian cancer cells. However, recent studies have revealed important roles of a variety of stromal cells in driving the aggressive behavior of ovarian cancer. Here, we discuss: (1) the significance of three major types of stromal cells in the progression of ovarian cancer; (2) how receptor/ligand-mediated interactions between ovarian cancer cells and stromal cells serve as focal points for therapeutic intervention; and (3) key examples of new-generation agents that target stromal cells.