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17 pages, 1564 KiB

Open AccessArticle

Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer

by Svetlana Magadeeva, Xueqian Qian, Nadine Korff, Inken Flörkemeier, Nina Hedemann, Christoph Rogmans, Michael Forster, Norbert Arnold, Nicolai Maass, Dirk O. Bauerschlag and Jörg P. Weimer

Int. J. Mol. Sci. 2023, 24(24), 17467; https://doi.org/10.3390/ijms242417467 - 14 Dec 2023

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Abstract

Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, [...] Read more.

Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, or indirectly by detecting mutations in the genes involved in HR. We show that HRD detection is also possible using high-resolution aCGH. A total of 30 OCs were analyzed retrospectively with high-resolution arrays as a test set and 19 OCs prospectively as a validation set. Mutation analysis was performed by HBOC TruRisk V2 panel to detect HR-relevant mutations. CNVs were clustered with respect to the involved HR genes versus the OC cases. In prospective validation, the HRD status determined by aCGH was compared with external HRD assessments. Two BRCA mutation carriers did not have HRD. OC could approximately differentiate into two groups with characteristic CNV patterns with different survival rates. Mutation frequencies have a linear regression on the HRD score. Mutations in individual HR-relevant genes do not always indicate HRD. This may depend on the mutation frequency in tumor cells. The aCGH shows the genomic scars of an HRD inexpensively and directly. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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17 pages, 2971 KiB

Open AccessArticle

Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer

by Yu Huang, Yali Fan, Ziyi Zhao, Xin Zhang, Katherine Tucker, Allison Staley, Hongyan Suo, Wenchuan Sun, Xiaochang Shen, Boer Deng, Stuart R. Pierce, Lindsay West, Yajie Yin, Michael J. Emanuele, Chunxiao Zhou and Victoria Bae-Jump

Int. J. Mol. Sci. 2023, 24(15), 12375; https://doi.org/10.3390/ijms241512375 - 3 Aug 2023

Cited by 4 | Viewed by 2444

Abstract

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and [...] Read more.

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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24 pages, 4510 KiB

Open AccessArticle

Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy

by Agnieszka Synowiec, Klaudia Brodaczewska, Gabriel Wcisło, Aleksandra Majewska, Agata Borkowska, Aleksandra Filipiak-Duliban, Aleksandra Gawrylak, Kinga Wilkus, Katarzyna Piwocka, Agata Kominek, Halina Waś, Sławomir Lewicki, Jacek Siewiera, Cezary Szczylik, Jolanta Szenajch, Jacek Z. Kubiak and Claudine Kieda

Int. J. Mol. Sci. 2023, 24(6), 5715; https://doi.org/10.3390/ijms24065715 - 16 Mar 2023

Cited by 3 | Viewed by 2488

Abstract

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) [...] Read more.

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO₂ = 1%) vs. normoxia (pO₂ = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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12 pages, 1492 KiB

Open AccessArticle

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment

by Marcus Vetter, Sylvia Stadlmann, Evelyne Bischof, Elena Laura Georgescu Margarint, Andreas Schötzau, Gad Singer, Viola Heinzelmann-Schwarz and Céline Montavon

Int. J. Mol. Sci. 2022, 23(22), 14242; https://doi.org/10.3390/ijms232214242 - 17 Nov 2022

Cited by 1 | Viewed by 2112

Abstract

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen [...] Read more.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II–IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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Review

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20 pages, 1347 KiB

Open AccessReview

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

by Klara Horackova, Marketa Janatova, Petra Kleiblova, Zdenek Kleibl and Jana Soukupova

Int. J. Mol. Sci. 2023, 24(23), 17020; https://doi.org/10.3390/ijms242317020 - 30 Nov 2023

Cited by 10 | Viewed by 1915

Abstract

Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC [...] Read more.

Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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17 pages, 768 KiB

Open AccessReview

Neuroendocrine Neoplasms of the Gastrointestinal Tract versus Neuroendocrine Neoplasms of the Gynaecological Tract—Comparison of the Risk Factors and Non-Surgical Treatment Efficacy

by Anna Lorenz, Sebastian Lenkiewicz, Mateusz Kozłowski, Sebastian Kwiatkowski and Aneta Cymbaluk-Płoska

Int. J. Mol. Sci. 2023, 24(7), 6853; https://doi.org/10.3390/ijms24076853 - 6 Apr 2023

Viewed by 1805

Abstract

Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a poor prognosis, especially when detected at an advanced stage. The basis of the treatment [...] Read more.

Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a poor prognosis, especially when detected at an advanced stage. The basis of the treatment is resection, and non-surgical treatments are also standard in the treatment process. The situation is similar in even rarer neuroendocrine tumours of the reproductive tract, which are associated with an equally poor prognosis. In this article, we focus on learning about the risk factors (including genetic mutations) that increase the risk of the disease and comparing the effectiveness of non-surgical treatments—chemotherapy, radiotherapy, peptide receptor radionuclide therapy, somatostatin analogues, and immunotherapy. The efficacy of these treatments varies, and immunotherapy appears to be a promising form of treatment; however, this requires further research. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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15 pages, 681 KiB

Open AccessReview

Changes in the Extracellular Matrix in Endometrial and Cervical Cancer: A Systematic Review

by Tjaša Padežnik, Anja Oleksy, Andrej Cokan, Iztok Takač and Monika Sobočan

Int. J. Mol. Sci. 2023, 24(6), 5463; https://doi.org/10.3390/ijms24065463 - 13 Mar 2023

Cited by 11 | Viewed by 3532

Abstract

Endometrial and cervical cancers are the two most common gynaecological malignancies and among the leading causes of death worldwide. The extracellular matrix (ECM) is an important component of the cellular microenvironment and plays an important role in developing and regulating normal tissues and [...] Read more.

Endometrial and cervical cancers are the two most common gynaecological malignancies and among the leading causes of death worldwide. The extracellular matrix (ECM) is an important component of the cellular microenvironment and plays an important role in developing and regulating normal tissues and homeostasis. The pathological dynamics of the ECM contribute to several different processes such as endometriosis, infertility, cancer, and metastasis. Identifying changes in components of ECM is crucial for understanding the mechanisms of cancer development and its progression. We performed a systematic analysis of publications on the topic of changes in the extracellular matrix in cervical and endometrial cancer. The findings of this systematic review show that matrix metalloproteinases (MMP) play an important role impacting tumour growth in both types of cancer. MMPs degrade various specific substrates (collagen, elastin, fibronectin, aggrecan, fibulin, laminin, tenascin, vitronectin, versican, nidogen) and play a crucial role in the basal membrane degradation and ECM components. Similar types of MMPs were found to be increased in both cancers, namely, MMP-1, MMP-2, MMP-9, and MMP-11. Elevated concentrations of MMP-2 and MMP-9 were correlated with the FIGO stage and are associated with poor prognosis in endometrial cancer, whereas in cervical cancer, elevated concentrations of MMP-9 have been associated with a better outcome. Elevated ADAMTS levels were found in cervical cancer tissues. Elevated disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) levels were also found in endometrial cancer, but their role is still unclear. Following these findings, this review reports on tissue inhibitors of ECM enzymes, MMPs, and ADAMTS. The present review demonstrates changes in the extracellular matrix in cervical and endometrial cancers and compared their effect on cancer development, progression, and patient prognosis. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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20 pages, 596 KiB

Open AccessReview

HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications

by Luca Giannella, Jacopo Di Giuseppe, Giovanni Delli Carpini, Camilla Grelloni, Mariasole Fichera, Gianmarco Sartini, Serena Caimmi, Leonardo Natalini and Andrea Ciavattini

Int. J. Mol. Sci. 2022, 23(23), 15022; https://doi.org/10.3390/ijms232315022 - 30 Nov 2022

Cited by 22 | Viewed by 6535

Abstract

Cervical cancer is the fourth most common cancer in women. It is the leading cause of female deaths in developing countries. Most of these cervical neoplasms are represented by squamous lesions. Cervical adenocarcinoma causes about a quarter of cervical cancers. In contrast to [...] Read more.

Cervical cancer is the fourth most common cancer in women. It is the leading cause of female deaths in developing countries. Most of these cervical neoplasms are represented by squamous lesions. Cervical adenocarcinoma causes about a quarter of cervical cancers. In contrast to squamous lesions, cervical glandular disease is HPV-negative in about 15–20% of cases. HPV-negative cervical adenocarcinomas typically present in advanced stages at clinical evaluation, resulting in a poorer prognosis. The overall and disease-free survival of glandular lesions is lower than that of squamous lesions. Treatment options require definitive treatments, as fertility-sparing is not recommended. Moreover, the impact of HPV vaccination and primary HPV screening is likely to affect these lesions less; hence, the interest in this challenging topic for clinical practice. An updated review focusing on clinical and molecular characterization, prognostic factors, and therapeutic options may be helpful for properly managing such cervical lesions. Full article

(This article belongs to the Special Issue Gynecological Cancer 2023)

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