Can Stemness and Chemoresistance Be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Roy, Lynn; Dahl, Karen D. Cowden

doi:10.3390/cancers10080241

Cited by 60 publications

(45 citation statements)

References 133 publications

(318 reference statements)

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“…Multiple signaling pathways have been described to play a role in the generation and maintenance of CSCs. Since CSCs are responsible for chemotherapy resistance, these pathways represent promising strategies to specifically target CSCs and overcome recurrence [157]. Treatments based on targeting developmental signaling pathways, including Wnt, hedgehog (Hh) and Notch, are being tested in clinical trials with variable results [158], probably due to their high crosstalk and pleiotropy.…”

Section: Therapies Targeting Signaling Pathways Involved In Ocsc Genementioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Muñoz-Galván

Carnero

2020

Cells

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Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are able to recapitulate new tumors. Recent studies have deepened the understanding of the biology of ovarian cancer stem cells and their special properties and have identified multiple markers and signaling pathways responsible for their self-renewal abilities. Targeting cancer stem cells represents the most promising strategy for overcoming therapy resistance and reducing mortality in ovarian cancer, but further efforts must be made to improve our understanding of the mechanisms involved in therapy resistance. In this review, we summarize our current knowledge about ovarian cancer stem cells, their involvement in metastasis and their interactions with the tumor microenvironment; we also discuss the therapeutic approaches that are being developed to target them to prevent tumor relapse.

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Section: Therapies Targeting Signaling Pathways Involved In Ocsc Genementioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Muñoz-Galván

Carnero

2020

Cells

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“…Several pathways, including those involving PI3/PTEN/AKT [80], JAK2/STAT3 [81][82][83], NFkB [84,85], Notch [86,87], Wnt [86,87], and Hedgehog [86,88] support the CSC phenotype and promote tumourigensis and therapy resistance in OC. Inhibiting these pathways in ovarian cell lines and OC animal models suppresses CSC numbers and makes these cells sensitive to chemotherapies [79].…”

Section: Epigenetic Changesmentioning

confidence: 99%

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

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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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...

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“…In OC, cancer SCs (CSCs) are reported to be important in tumor initiation, dissemination, and recurrence, and targeting CSC components is an endeavor of OC therapy [7][8][9]. Identifying CSCs relies on the presence of SC markers, and in OC, many biomarkers can be used to confirm the presence of CSCs.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma

Liu

Chen

Fan

et al. 2020

IJMS

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Cancer stem cells (CSCs) are considered to be the origin of ovarian cancer (OC) development, recurrence, and chemoresistance. We investigated changes in expression levels of the CSC biomarker, cluster of differentiation 133 (CD133), from primary OC cell lines to induction of CSC-spheres in an attempt to explore the mechanisms related to modulation of stemness, drug resistance, and tumorigenesis in CSCs, thus facilitating the search for new therapeutics for OC. The effect of CD133 overexpression on the induction of CSC properties was evaluated by sphere-forming assays, RT-qPCR, flow cytometry, cell viability assays, and in vivo xenograft experiments. Moreover, the potential signaling molecules that participate in CD133 maintenance of stemness were screened by RNA-sequencing. CD133 expression was upregulated during OCSC induction and chemotherapeutic drug treatment over time, which increased the expressions of stemness-related markers (SOX2, OCT4, and Nanog). CD133 overexpression also promoted tumorigenesis in NOD/SCID mice. Several signalings were controlled by CD133 spheres, including extracellular matrix receptor interactions, chemokine signaling, and Wnt signaling, all of which promote cell survival and cell cycle progression. Our findings suggest that CD133 possesses the ability to maintain functional stemness and tumorigenesis of OCSCs by promoting cell survival signaling and may serve as a potential target for stem cell-targeted therapy of OC.

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Can Stemness and Chemoresistance Be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Cited by 60 publications

References 133 publications

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

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

Characteristics of CD133-Sustained Chemoresistant Cancer Stem-Like Cells in Human Ovarian Carcinoma

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