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

Abstract

Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

“…The identified transformed clones were able to grow in low attachment conditions and establish tumors in serial transplantations over animal models. OCSCs also possess other stemness properties, such as chemoresistance, increased expression of stem-related genes (such as OCT 4, NANOG or NESTIN ) and elevated levels of stem cell surface markers (such as CD44 and CD117) [ 16 , 35 , 36 ]. Stem cells have been identified in the coelomic epithelium of mouse ovaries [ 37 ] but also in a transitional region between the ovarian surface epithelium, the mesothelium and the tubal epithelium, known as the hilum [ 38 ].…”

Current Ovarian Cancer Maintenance Strategies and Promising New Developments

“…Mitochondria-associated granulocyte colony-stimulating factor stimulating protein (Magmas) is a ROS scavenger, that is also overexpressed in ovarian cancer cells. Magmas inhibitor BT#9 was able to sensitize an ovarian cancer cell line to carboplatin 90 . However, targeting cancer cell metabolism in the clinic has been largely unsuccessful either due to a lack of efficacy or safety (reviewed in 91 ).…”

CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells

“…Epithelial ovarian cancer (EOC) is a common gynecologic cancer with the highest death rate, and it is frequently resistant to conventional cancer therapies (1). The major cause of the poor prognosis of ovarian cancer is the presence of cancer stem cells (CSCs), a heterogeneous cancer-cell population (2,3). Improving the therapeutic efficacy of conventional cancer therapy requires identifying diagnostic and/or therapeutic markers that target CSCs.…”