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Review
. 2020 Mar 14;9(3):719.
doi: 10.3390/cells9030719.

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

Nuzhat Ahmed  1   2   3   4 , Elif Kadife  1 , Ali Raza  1   2 , Mary Short  5 , Paul T Jubinsky  5 , George Kannourakis  1   2
Affiliations
Review

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

Nuzhat Ahmed et al. Cells. .

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.

Keywords: magmas; ovarian cancer; treatment.

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Conflict of interest statement

M.S. has a financial interest in compound BT#9. P.J. has a financial interest in compound BT#9.

Figures

Figure 1
Figure 1
Magmas expression is higher in HGSOC than benign serous tumours. Representative immunohistochemistry images of Magmas in a (A) benign serous tumour and a (B) HGSOC. Benign (n = 8) and HGSOC (n = 17) were obtained from patients diagnosed with OC undertaking surgery at The Royal Women’s Hospital after obtaining written consent under protocols approved by the Human Research and Ethics Committee (Ethics approval #09/09) of the Royal Women’s Hospital, Melbourne, Australia. Benign tumours were from patients undertaking total abdominal hysterectomy or bilateral salpingo-oophorectomy due to pre-diagnosed medical conditions. Immunohistochemistry on paraffin-embedded human serous ovarian tumours was performed as described previously [83]. (C) Negative controls were prepared by incubating tissue sections without the primary antibody followed by the secondary antibody. Stained slides were scanned at 20× magnification using Leica EVOS FL Auto 2 microscope (Thermo Fisher). Sections were assessed microscopically for positive DAB staining. Scale bar = 100 µm, Magnification is 20×.
Figure 2
Figure 2
Co-localization of Magmas with the mitochondrial fluorescent dye marker AF488 in OV90, HEY and OVCAR5 human ovarian cancer cell lines. OV90, HEY and OVCAR5 cells were fixed with 4% paraformaldehyde, and probed with Magmas targeting primary antibody [83] and co-stained with mitochondria specific primary followed by respective secondary antibodies (AF555, AF488, Life Technologies). DAPI (4′,6-diamidino-2-phenylindole) (Invitrogen, Carlsbad, USA) was used to stain cellular nuclei. Fluorescence imaging was performed using Leica EVOS FL Auto 2 microscope. Scale bar = 75 µm, Magnification is 40×.
Figure 3
Figure 3
The mRNA expression of Magmas, ERCC1 and OCT4 in SKOV3 and OVCAR5 ovarian cancer cell lines. Magmas, ERCC1 and OCT4 mRNA expression in SKOV3 and OVCAR5 cells were performed after treatment with IC50 doses of cisplatin or paclitaxel as described previously [83,123]. The relative expression of gene of interest was normalized to housekeeping 18S gene. Data are shown as the mean of +SEM (n = 3). Significance between the groups was deduced by One-way ANOVA and is indicated by * p > 0.05, ** p > 0.01, *** p < 0.001, **** p < 0.0001.
Figure 4
Figure 4
Magmas expression was induced in xenografts treated with chemotherapy. Animal experiment was performed in strict accordance with the recommendation in the Guide for the Care and Use of Laboratory Animals of the National Health and Medical Research Council of Australia. The experimental protocol was approved by the University of Melbourne Animal Ethics Committee (Project-1413207.1). Female Balb/c nu/nu mice (age 6–8 weeks) were injected intraperitoneally (i.p) with 5 × 106 ovarian cancer HEY cells. Paclitaxel treatment started 19 days after cancer cell induction and mice received 2 rounds of paclitaxel treatment once a week at 15 mg/kg dose before being culled at the same time as control mice. Immunohistochemistry on paraffin-embedded tumours was performed as described previously [57,81,82,83]. Magmas expression was significantly lower in (A) untreated tumours compared to those that were (B) treated with paclitaxel. (C) Negative controls were prepared by incubating tissue sections without the primary antibody followed by the secondary antibody. Stained slides were scanned at 20× magnification using Leica EVOS FL Auto 2 microscope (Thermo Fisher). (D) Sections were assessed microscopically and quantitatively for positive DAB staining using Imagej FIJI. Scale bar = 100 µm. Significance is indicated by * p < 0.05 by T-test.
Figure 5
Figure 5
Sensitivity of OV90 parental (control) and carboplatin resistant (CBPR) ovarian cancer cells to carboplatin and Magmas inhibitor BT#9. OV90 parental control and OV90 CBPR cells (5 × 105 cells/well) were seeded and treated with varying concentrations of carboplatin and BT#9 drugs (carboplatin 72 h or BT#9 48 h). Cell viability was checked by WST-1 assay kit was used according to manufacturer’s instructions. (A) IC50 values of OV90 control cells and OV90 CBPR cells in response to Carboplatin; (B) IC50 values of OV90 control cells and OV90 CBPR cells in response to BT#9. Assays were conducted three times in triplicate.
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