International Journal of Molecular Sciences

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Open AccessEditorial

Ovarian Cancer: Advances in Pathophysiology and Therapies

by Giovanni Tossetta and Annalisa Inversetti

Int. J. Mol. Sci. 2023, 24(10), 8930; https://doi.org/10.3390/ijms24108930 - 18 May 2023

Cited by 4 | Viewed by 1512

Abstract

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled “Ovarian Cancer: Advances in Pathophysiology and Therapies” [...] Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

Research

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18 pages, 15523 KiB

Open AccessArticle

Effects of Resveratrol on In Vivo Ovarian Cancer Cells Implanted on the Chorioallantoic Membrane (CAM) of a Chicken Embryo Model

by Kenny Chitcholtan, Melanie Singh, Alex Tino, Ashley Garrill and Peter Sykes

Int. J. Mol. Sci. 2024, 25(8), 4374; https://doi.org/10.3390/ijms25084374 - 16 Apr 2024

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Abstract

Ovarian cancer poses a significant threat to patients in its advanced stages, often with limited treatment options available. In such cases, palliative management becomes the primary approach to maintaining a reasonable quality of life. Therefore, the administration of any medication that can benefit [...] Read more.

Ovarian cancer poses a significant threat to patients in its advanced stages, often with limited treatment options available. In such cases, palliative management becomes the primary approach to maintaining a reasonable quality of life. Therefore, the administration of any medication that can benefit patients without a curative option holds potential. Resveratrol, a natural compound known for its in vitro anticancer activities, has generated contrasting results in vivo and human studies. In this study, we aimed to assess the anticancer effects of resveratrol on ovarian cancer cells grown on the chorioallantoic membrane (CAM) of chicken embryos. Two ovarian cancer cell lines, OVCAR-8 and SKOV-3, were cultured in collagen scaffolds for four days before being implanted on the CAM of chicken embryos on day 7. Different doses of resveratrol were applied to the CAM every two days for six days. Subsequently, CAM tissues were excised, fixed, and subjected to histological analysis. Some CAM tumours were extracted to analyse proteins through Western blotting. Our findings indicate that specific doses of resveratrol significantly reduce angiogenic activities, pNF-κB levels, and SLUG protein levels by using immunohistochemistry. These results suggest that resveratrol may have the potential to impact the behaviour of ovarian cancer CAM tumours, thereby warranting further consideration as a complementary treatment option for women with incurable ovarian cancer. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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16 pages, 2871 KiB

Open AccessArticle

Transcriptomic Analysis of the Aged Nulliparous Mouse Ovary Suggests a Stress State That Promotes Pro-Inflammatory Lipid Signaling and Epithelial Cell Enrichment

by Carlos Chacón, Constanza Mounieres, Sandra Ampuero and Ulises Urzúa

Int. J. Mol. Sci. 2024, 25(1), 513; https://doi.org/10.3390/ijms25010513 - 30 Dec 2023

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Abstract

Ovarian cancer (OC) incidence and mortality peaks at post-menopause while OC risk is either reduced by parity or increased by nulliparity during fertile life. The long-term effect of nulliparity on ovarian gene expression is largely unknown. In this study, we describe a bioinformatic/data-mining [...] Read more.

Ovarian cancer (OC) incidence and mortality peaks at post-menopause while OC risk is either reduced by parity or increased by nulliparity during fertile life. The long-term effect of nulliparity on ovarian gene expression is largely unknown. In this study, we describe a bioinformatic/data-mining analysis of 112 coding genes upregulated in the aged nulliparous (NP) mouse ovary compared to the aged multiparous one as reference. Canonical gene ontology and pathway analyses indicated a pro-oxidant, xenobiotic-like state accompanied by increased metabolism of inflammatory lipid mediators. Up-regulation of typical epithelial cell markers in the aged NP ovary was consistent with synchronized overexpression of Cldn3, Ezr, Krt7, Krt8 and Krt18 during the pre-neoplastic phase of mOSE cell cultures in a former transcriptome study. In addition, 61/112 genes were upregulated in knockout mice for Fshr and for three other tumor suppressor genes (Pten, Cdh1 and Smad3) known to regulate follicular homeostasis in the mammalian ovary. We conclude that the aged NP ovary displays a multifaceted stress state resulting from oxidative imbalance and pro-inflammatory lipid signaling. The enriched epithelial cell content might be linked to follicle depletion and is consistent with abundant clefts and cysts observed in aged human and mouse ovaries. It also suggests a mesenchymal-to-epithelial transition in the mOSE of the aged NP ovary. Our analysis suggests that in the long term, nulliparity worsens a variety of deleterious effects of aging and senescence thereby increasing susceptibility to cancer initiation in the ovary. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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14 pages, 1873 KiB

Open AccessArticle

Evaluating the Utility of ctDNA in Detecting Residual Cancer and Predicting Recurrence in Patients with Serous Ovarian Cancer

by Jie Wei Zhu, Fabian Wong, Agata Szymiczek, Gabrielle E. V. Ene, Shiyu Zhang, Taymaa May, Steven A. Narod, Joanne Kotsopoulos and Mohammad R. Akbari

Int. J. Mol. Sci. 2023, 24(18), 14388; https://doi.org/10.3390/ijms241814388 - 21 Sep 2023

Cited by 5 | Viewed by 1177

Abstract

Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many [...] Read more.

Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many cases, these cells are occult and are not visible to the surgeon. Analysis of circulating tumour DNA in the blood (ctDNA) may offer a sensitive method to predict the presence of occult (non-visible) residual disease after surgery and may help predict disease recurrence. We assessed 48 women diagnosed with serous ovarian cancer (47 high-grade and 1 low-grade) for visible residual disease and for ctDNA. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. We sequenced DNA samples for 59 breast and ovarian cancer driver genes. The plasma sample was collected after surgery and before initiating chemotherapy. We compared survival in women with no residual disease, with and without a positive plasma ctDNA test. We found tumour-specific variants (TSVs) in cancer cells from 47 patients, and these variants were sought in ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Thirty-one patients (65.9%) had no visible residual disease; of these, 24 (77.4%) patients had detectable ctDNA. Of the patients with no visible residual disease, those patients with detectable ctDNA had higher mortality (20 of 27 died) than those without detectable ctDNA (3 of 7 died) (HR 2.32; 95% CI: 0.67–8.05), although this difference was not statistically significant (p = 0.18). ctDNA in post-surgical serum samples may predict the presence of microscopic residual disease and may be a predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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11 pages, 1225 KiB

Open AccessArticle

SYNE1 Mutation Is Associated with Increased Tumor Mutation Burden and Immune Cell Infiltration in Ovarian Cancer

by Laura M. Harbin, Nan Lin, Frederick R. Ueland and Jill M. Kolesar

Int. J. Mol. Sci. 2023, 24(18), 14212; https://doi.org/10.3390/ijms241814212 - 18 Sep 2023

Cited by 2 | Viewed by 1060

Abstract

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation [...] Read more.

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the SYNE1 mutation frequency, association with TMB, and downstream effects of SYNE1 mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer Genome Atlas (TCGA). Bioinformatics analyses were performed. In our cohort of 50 patients, 16 had a SYNE1 mutation, and 15 had recurrent disease. Median TMB for SYNE1 mutated patients was 25 compared to 7 for SYNE1 wild-type patients (p < 0.0001). Compared to the TCGA cohort, our cohort had higher SYNE1 mutation rates (32% vs. 6%, p < 0.001). Gene expression related to immune cell trafficking, inflammatory response, and immune response (z > 2.0) was significantly increased in SYNE1 mutated patients. SYNE1 mutation is associated with increased TMB and immune cell infiltration in ovarian cancer and may serve as an additional biomarker for immunotherapy response. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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18 pages, 21326 KiB

Open AccessArticle

Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade

by Adel Alblihy, Reem Ali, Mashael Algethami, Alison A. Ritchie, Ahmed Shoqafi, Shatha Alqahtani, Katia A. Mesquita, Michael S. Toss, Paloma Ordóñez-Morán, Jennie N. Jeyapalan, Lodewijk Dekker, Martina Salerno, Edgar Hartsuiker, Anna M. Grabowska, Emad A. Rakha, Nigel P. Mongan and Srinivasan Madhusudan

Int. J. Mol. Sci. 2023, 24(13), 10966; https://doi.org/10.3390/ijms241310966 - 30 Jun 2023

Cited by 1 | Viewed by 1512

Abstract

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer [...] Read more.

The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11^+/⁻ cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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Review

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15 pages, 1140 KiB

Open AccessReview

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

by Makenzie Vorderbruggen, Carlos A. Velázquez-Martínez, Amarnath Natarajan and Adam R. Karpf

Int. J. Mol. Sci. 2024, 25(10), 5067; https://doi.org/10.3390/ijms25105067 - 7 May 2024

Viewed by 488

Abstract

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development [...] Read more.

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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17 pages, 1984 KiB

Open AccessReview

Role of SLC7A11/xCT in Ovarian Cancer

by Sonia Fantone, Federica Piani, Fabiola Olivieri, Maria Rita Rippo, Angelo Sirico, Nicoletta Di Simone, Daniela Marzioni and Giovanni Tossetta

Int. J. Mol. Sci. 2024, 25(1), 587; https://doi.org/10.3390/ijms25010587 - 2 Jan 2024

Cited by 1 | Viewed by 1495

Abstract

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, [...] Read more.

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the

X_{c}^{-}

system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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14 pages, 1070 KiB

Open AccessReview

Recent Insight about HE4 Role in Ovarian Cancer Oncogenesis

by Emanuela Anastasi, Antonella Farina, Teresa Granato, Flavia Colaiacovo, Beatrice Pucci, Sara Tartaglione and Antonio Angeloni

Int. J. Mol. Sci. 2023, 24(13), 10479; https://doi.org/10.3390/ijms241310479 - 22 Jun 2023

Cited by 3 | Viewed by 3121

Abstract

Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in [...] Read more.

Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in OC as it has been implicated not only in OC diagnosis but also in the prognosis and recurrence of this lethal neoplasm, actually acting as a clinical biomarker. There are several evidence about the predictive power of HE4 clinically, conversely less has been described concerning its role in OC oncogenesis. Based on these considerations, the main goal of this review is to clarify the role of HE4 in OC proliferation, angiogenesis, metastatization, immune response and also in the development of targeted therapy. Through a deeper understanding of its functions as a key molecule in the oncogenetic processes underlying OC, HE4 could be possibly considered as an essential resource not only for diagnosis but also for prognosis and therapy choice. Full article

(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)

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