Therapeutic Targeting of Collective Invasion in Ovarian Cancer

Abstract

Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. Each histotype differs in etiology, pathogenesis, molecular biology, risk factors, and prognosis. Furthermore, the origin of ovarian cancer remains unclear, with ovarian involvement secondary to the contribution of other gynaecological tissues. Despite these complexities, the disease is often treated as a single entity, resulting in minimal improvement to survival rates since the introduction of platinum-based chemotherapy over 30 years ago. Despite concerted research efforts, ovarian cancer remains one of the most difficult cancers to detect and treat, which is in part due to the unique mode of its dissemination. Ovarian cancers tend to invade locally to neighbouring tissues by direct extension from the primary tumour, and passively to pelvic and distal organs within the peritoneal fluid or ascites as multicellular spheroids. Once at their target tissue, ovarian cancers, like most epithelial cancers including colorectal, melanoma, and breast, tend to invade as a cohesive unit in a process termed collective invasion, driven by specialized cells termed "leader cells". Emerging evidence implicates leader cells as essential drivers of collective invasion and metastasis, identifying collective invasion and leader cells as a viable target for the management of metastatic disease. However, the development of targeted therapies specifically against this process and this subset of cells is lacking. Here, we review our understanding of metastasis, collective invasion, and the role of leader cells in ovarian cancer. We will discuss emerging research into the development of novel therapies targeting collective invasion and the leader cell population.

Keywords: invasion; leader cells; metastasis; ovarian cancer; therapies.

Figure 1

Metastasis model in ovarian cancer. A schematic model of ovarian cancer progression and dissemination. Ovarian cancer cells in the primary tumour acquire a unique expression profile and are exfoliated from the primary tumour site into the ascites. Ovarian cancer cells which have shed form multicellular aggregates are termed spheroids.erin. Spheres are carried passively within the peritoneum by the peritoneal fluid or ascites where they seed multiple distal metastasis by attaching to and clearing the mesothelial lining.

Figure 2

Collective invasion in epithelial ovarian cancer. A schematic representation of the metastatic spread of ovarian tumour cells. Ovarian cancer spheres diffuse throughout the peritoneal cavity. Upon their attachment to the mesothelial layer, epithelial genes are activated. Specialized leader cells transiently express basal epithelial and luminal epithelium markers and displace the target mesothelium via the formation of actin-rich invadopodia, where trailing cells follow to colonize surrounding tissues.