Research

Jump to: Review

20 pages, 1734 KiB

Open AccessArticle

The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells

by Chiara Bellio, Celeste DiGloria, David R. Spriggs, Rosemary Foster, Whitfield B. Growdon and Bo R. Rueda

Cancers 2019, 11(11), 1678; https://doi.org/10.3390/cancers11111678 - 29 Oct 2019

Cited by 23 | Viewed by 6888

Abstract

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the [...] Read more.

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Graphical abstract

18 pages, 3220 KiB

Open AccessArticle

4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

by Noor A. Lokman, Zoe K. Price, Emily K. Hawkins, Anne M. Macpherson, Martin K. Oehler and Carmela Ricciardelli

Cancers 2019, 11(8), 1187; https://doi.org/10.3390/cancers11081187 - 15 Aug 2019

Cited by 26 | Viewed by 5348

Abstract

We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome [...] Read more.

We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

16 pages, 1945 KiB

Open AccessArticle

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

by Sarah J. Kitson, Matthew Rosser, Deborah P. Fischer, Kay M. Marshall, Robert B. Clarke and Emma J. Crosbie

Cancers 2019, 11(5), 653; https://doi.org/10.3390/cancers11050653 - 11 May 2019

Cited by 41 | Viewed by 4003

Abstract

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully [...] Read more.

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDH^high) and CD133^+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDH^high and CD133^+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDH^high cells demonstrated greater endometrial cancer stem cell activity than CD133^+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

Review

Jump to: Research

20 pages, 1530 KiB

Open AccessEditor’s ChoiceReview

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

by Vaishnavi Muralikrishnan, Thomas D. Hurley and Kenneth P. Nephew

Cancers 2020, 12(4), 961; https://doi.org/10.3390/cancers12040961 - 13 Apr 2020

Cited by 35 | Viewed by 7715

Abstract

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the [...] Read more.

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

16 pages, 731 KiB

Open AccessReview

Ovarian Cancer—Why Lipids Matter

by Guangyuan Zhao, Horacio Cardenas and Daniela Matei

Cancers 2019, 11(12), 1870; https://doi.org/10.3390/cancers11121870 - 26 Nov 2019

Cited by 47 | Viewed by 6748

Abstract

This review highlights recent advances in the understanding of the relevance of altered lipid metabolic pathways contributing to the poor prognosis of high grade serous ovarian cancer, as they relate to cancer metastasis and cancer stemness. Increased lipid uptake regulated by the receptor [...] Read more.

This review highlights recent advances in the understanding of the relevance of altered lipid metabolic pathways contributing to the poor prognosis of high grade serous ovarian cancer, as they relate to cancer metastasis and cancer stemness. Increased lipid uptake regulated by the receptor CD36 and the transport protein FABP4 has been implicated in ovarian cancer metastasis. The symbiotic relationship between ovarian cancer cells and adipocytes was shown to be important for sustaining widespread peritoneal and omental metastasis. Increased lipogenesis dependent on the fatty acid desaturase SCD1 was detected in ovarian cancer stem cells. Furthermore, response to therapy, specifically to platinum, was linked to increased fatty acid biogenesis, while the survival of drug tolerant cells was shown to depend on lipid peroxidation. These recent findings suggest that lipids are necessary elements supporting oncogenic signaling and the energetic needs of rapidly proliferating cancer cells. New strategies targeting key enzymes involved in lipid uptake or utilization in cancer cells have been shown to exert anti-tumor effects and are being developed as cancer interventions in combination with chemotherapy or immunotherapy. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

18 pages, 4933 KiB

Open AccessReview

Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications

by Gaia Giannone, Laura Attademo, Giulia Scotto, Sofia Genta, Eleonora Ghisoni, Valentina Tuninetti, Massimo Aglietta, Sandro Pignata and Giorgio Valabrega

Cancers 2019, 11(11), 1820; https://doi.org/10.3390/cancers11111820 - 19 Nov 2019

Cited by 59 | Viewed by 5043

Abstract

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature [...] Read more.

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature cancer cells, represent a potential field of expansion for drug development. The aim of this review is to characterize the role of eCSC in EC, their features and how they could be targeted. CSC are involved in progression, invasiveness and metastasis (though epithelial to mesenchimal transition, EMT), as well as chemoresistance in EC. Nevertheless, isolation of eCSC is still controversial. Indeed, CD133, Aldheyde dehydrogenase (ALDH), CD117, CD55 and CD44 are enriched in CSCs but there is no universal marker nowadays. The most frequently activated pathways in eCSC are Wingless-INT (Wnt)/β-catenin, Notch1, and Hedghog, with a high expression of self-renewal transcription factors like Octamer binding transcription factor 4 (OCT), B Lymphoma Mo-MLV Insertion Region 1 Homolog (BMI1), North American Network Operations Group Homebox protein (NANOG), and SRY-Box 2 (SOX2). These pathways have been targeted with selective drugs alone or in combination with chemotherapy and immunotherapy. Unfortunately, although preclinical results are encouraging, few clinical data are available. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

17 pages, 2048 KiB

Open AccessReview

Enriching Personalized Endometrial Cancer Research with the Harmonization of Biobanking Standards

by Meera Adishesh and Dharani K. Hapangama

Cancers 2019, 11(11), 1734; https://doi.org/10.3390/cancers11111734 - 05 Nov 2019

Cited by 11 | Viewed by 2365

Abstract

Endometrial cancer is the commonest gynecological cancer, with an incidence predicted to escalate by a further 50–100% before 2025, due to the rapid rise in risk factors such as obesity and increased life expectancy. Endometrial cancer associated mortality is also rising, depicting the [...] Read more.

Endometrial cancer is the commonest gynecological cancer, with an incidence predicted to escalate by a further 50–100% before 2025, due to the rapid rise in risk factors such as obesity and increased life expectancy. Endometrial cancer associated mortality is also rising, depicting the need for translatable research to improve our understanding of the disease. Rapid translation of scientific discoveries will facilitate the development of new diagnostic, prognostic and therapeutic strategies. Biobanks play a vital role in providing biospecimens with accompanying clinical data for personalized translational research. Wide variation in collection, and pre-analytic variations in processing and storage of bio-specimens result in divergent and irreproducible data from multiple studies that are unsuitable for collation to formulate robust conclusions. Harmonization of biobanking standards is thus vital, in facilitating international multi-center collaborative studies with valuable outcomes to improve personalized treatments. This review will detail the pitfalls in the biobanking of biosamples from women with cancer in general, and describe the recent international harmonization project that developed standardized research tools to overcome these challenges and to enhance endometrial cancer research, which will facilitate future development of personalized novel diagnostic strategies and treatments. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

► Show Figures

Figure 1

19 pages, 280 KiB

Open AccessFeature PaperReview

Unique Molecular Features in High-Risk Histology Endometrial Cancers

by Pooja Pandita, Xiyin Wang, Devin E. Jones, Kaitlyn Collins and Shannon M. Hawkins

Cancers 2019, 11(11), 1665; https://doi.org/10.3390/cancers11111665 - 27 Oct 2019

Cited by 10 | Viewed by 3166

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with [...] Read more.

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)

Journal Menu

Journal Browser

Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI