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.

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…In contrast, OC cells adhesion to sub-mesothelial collagen matrix, occurs via α2β1 and α3β1 integrins [96,97]. A population of OC cells expressing keratin 14 appear to initiate the invasion process [98,99].…”

Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells

“…Ovarian cancer (OC) is the most lethal of the gynecological malignancies, with a ~70% five-year mortality [1]. Characterised by asymptomatic progression, patients typically present with advanced, extensively disseminated cancer, multiple tumor deposits, and ascitic fluid in the peritoneal cavity.…”

“…Unlike the majority of epithelial tumor types, the primary mode for metastatic OC spread involves the exfoliation of heterogeneous, multicellular aggregates from the primary tumor site. Spheroids passively disseminate throughout the peritoneal cavity; on reaching a permissive environment, they attach and superficially invade through the mesothelial lining and implant onto adjacent organs [1,2,3,4]. Spheroids also persist in the peritoneal cavity following therapy, suggesting their potential involvement in tumor recurrence.…”

Nanodrug Delivery Systems for the Treatment of Ovarian Cancer

“…However, conventional treatment has its own share of drawbacks, including toxicities and subsequent disease relapse, due to the development of multidrug resistance. In addition, the chemodrug is not specific for OC destruction, hence exhibiting dose cytotoxicity [10][11][12]. Furthermore, the long-term prognosis is usually adversative with expression and development of chemoresistant tumours.…”