Ovarian cancer stem cells: Can targeted therapy lead to improved progression-free survival?

Abstract

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based chemotherapy. Newer therapies including limited targeted agents and intraperitoneal delivery of chemotherapeutic drugs have improved disease-free intervals, but failed to yield long-lasting cures in most patients. Chemotherapeutic resistance, particularly in the recurrent setting, plagues the disease. Targeting the pathways and mechanisms behind the development of chemoresistance in ovarian cancer could lead to significant improvement in patient outcomes. In many malignancies, including blood and other solid tumors, there is a subgroup of tumor cells, separate from the bulk population, called cancer stem cells (CSCs). These CSCs are thought to be the cause of metastasis, recurrence and resistance. However, to date, ovarian CSCs have been difficult to identify, isolate, and target. It is felt by many investigators that finding a putative ovarian CSC and a chemotherapeutic agent to target it could be the key to a cure for this deadly disease. This review will focus on recent advances in this arena and discuss some of the controversies surrounding the concept.

The role of Notch signaling in the mammalian ovary

“…Difficulty in treating ovarian tumors has at least in part been attributed to the formation or maintenance of cancer stem cells (Jordan et al 2006, Shah et al 2013, Walters Haygood et al 2014). Stem cell factors such as Nanog and Oct4 have been shown to be upregulated by the overexpression of NICD3 in cells of the ovarian surface epithelium, suggesting a potential role in supporting an undifferentiated cellular state (Park et al 2010).…”

Molecular staging of gynecological cancer: What is the future?

“…Trials of CD44 ligands conjugated to cisplatin and paclitaxel in intraperitoneal OC murine models have shown decreased growth and weights of tumor [56]. Imatinib, a KIT tyrosine kinase, showed disappointing results in the treatment of recurrent platinum-resistant LGSOC with no RR, one of 11 patients with SD for 7.3 months and the rest with PD [56].…”

“…Imatinib, a KIT tyrosine kinase, showed disappointing results in the treatment of recurrent platinum-resistant LGSOC with no RR, one of 11 patients with SD for 7.3 months and the rest with PD [56]. …”

Overexpression of the cancer stem cell marker CD117 predicts poor prognosis in epithelial ovarian cancer patients: evidence from meta-analysis

“…Recently, accumulating studies have identified CSCs as a crucial driving factor for EOC tumorigenesis and metastasis 7. Moreover, emerging evidence also suggests that CSCs contribute to chemotherapy resistance in EOC patients, thereby leading to worse disease-free survival (DFS) 8,9. Experimental studies have revealed that CSC-induced malignant characteristics may be conditioned by the activation of oncogenic signaling pathways (such as Wnt signaling) or the epithelial–mesenchymal transition pathway 10,11.…”