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Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 28703

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Dr. Kuo-Hu Chen

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1. Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, Taipei 231, Taiwan
2. School of Medicine, Tzu-Chi University, Hualien 970, Taiwan
Interests: gynecologic cancer; endometriosis; PCOS; target therapy
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Special Issue Information

Dear Colleagues,

Women's health is a major topic of concern all over the world. During their lives, women may encounter invasion of gynecologic malignancies including ovarian cancer, cervical cancer, uterine corpus, and endometrial cancer, many of which may be unexpected and have huge consequences on patients and their families. Gynecologic malignancy per se and relevant complications significantly influence the life span and quality of affected women. Other benign gynecologic diseases, such as endometriosis and polycystic ovary syndrome (PCOS), can bring about negative effects in women's daily lives. Healthcare related to these has been an important issue and remains to be explored. This Special Issue plans to give an overview of the most recent advances in the underlying molecular and cellular mechanisms of gynecologic malignancies, benign diseases, and their medications. It solicits any original contributions and reviews that explore the nature of gynecologic malignancies and benign diseases, associated therapies, and health impacts on women in different countries and communities. Studies discussing the health issues mentioned above are suitable for consideration in the Special Issue. Advances or any cutting-edge research in affected women’s healthcare are especially welcomed to be published. The listed topics suggest just a few of the many possibilities. Potential topics include but are not limited to gynecologic malignancies, endometrial cancer, ovarian cancer, cervical cancer, uterine cancer, chemotherapy, target therapy, tumor markers, benign gynecologic diseases, endometriosis, and polycystic ovary syndrome.

Dr. Kuo-Hu Chen
Guest Editor

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Keywords

gynecologic malignancies
endometrial cancer
ovarian cancer
cervical cancer
uterine cancer
chemotherapy
target therapy
tumor marker
benign gynecologic diseases
endometriosis
polycystic ovary syndrome

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Published Papers (8 papers)

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Research

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16 pages, 3422 KiB

Open AccessArticle

Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production

by Jiayu Xu, Xinyu Shao, Haozhe Zeng, Chengxi Wang, Jiayi Li, Xiaoqin Peng, Yong Zhuo, Lun Hua, Fengyan Meng and Xingfa Han

Int. J. Mol. Sci. 2023, 24(19), 14922; https://doi.org/10.3390/ijms241914922 - 5 Oct 2023

Viewed by 1604

Abstract

Increased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other’s production in a feed-forward loop, and (2) circulating FGF21 and GCs are parallelly increased in menopausal women and ovariectomized mice, we thus hypothesized that elevation of hepatic FGF21 secretion causes increased GGs production in estrogen-depleted females. Using the ovariectomized mice as a model for menopausal women, we found that ovariectomy (OVX) increased circulating corticosterone levels, which in turn increased visceral adipose Hsd11b1 expression, thus causing visceral obesity in females. In contrast, liver-specific FGF21 knockout (FGF21 LKO) completely reversed OVX-induced high GCs and high visceral adipose Hsd11b1 expression, thus abrogating OVX-induced obesity in females. Even though FGF21 LKO failed to rescue OVX-induced dyslipidemia, hepatic steatosis, and insulin resistance. What’s worse, FGF21 LKO even further exacerbated whole-body glucose metabolic dysfunction as evidenced by more impaired glucose and pyruvate tolerance and worsened insulin resistance. Mechanically, we found that FGF21 LKO reduced circulating insulin levels, thus causing the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes in OVX mice. Collectively, our results suggest that liver FGF21 plays an essential role in mediating OVX-induced central obesity by promoting GC production. However, lack of liver FGF21 signaling reduces insulin production and in turn causes the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes, highlighting a detrimental role for hepatic FGF21 signals in mediating the development of central obesity but a beneficial role in preventing metabolic abnormality from further exacerbation in estrogen-depleted females. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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15 pages, 3710 KiB

Open AccessArticle

Quinagolide Treatment Reduces Invasive and Angiogenic Properties of Endometrial Mesenchymal Stromal Cells

by Corinne Iampietro, Alessia Brossa, Stefano Canosa, Stefania Tritta, Glenn E. Croston, Torsten Michael Reinheimer, Filippo Bonelli, Andrea Roberto Carosso, Gianluca Gennarelli, Stefano Cosma, Chiara Benedetto, Alberto Revelli and Benedetta Bussolati

Int. J. Mol. Sci. 2022, 23(3), 1775; https://doi.org/10.3390/ijms23031775 - 4 Feb 2022

Cited by 4 | Viewed by 2320

Abstract

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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Review

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12 pages, 1145 KiB

Open AccessReview

The Role of Peroxisome Proliferator-Activated Receptors in Endometrial Cancer

by Iason Psilopatis, Kleio Vrettou, Constantinos Troungos and Stamatios Theocharis

Int. J. Mol. Sci. 2023, 24(11), 9190; https://doi.org/10.3390/ijms24119190 - 24 May 2023

Cited by 6 | Viewed by 1842

Abstract

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins which regulate gene expression. In order to investigate the role of PPARs in endometrial cancer, we conducted a literature review using the MEDLINE and LIVIVO databases and were able to identify 27 relevant studies published between 2000 and 2023. The PPARα and PPARβ/δ isoforms seemed to be upregulated, whereas PPARγ levels were reported to be significantly lower in endometrial cancer cells. Interestingly, PPAR agonists were found to represent potent anti-cancer therapeutic alternatives. In conclusion, PPARs seem to play a significant role in endometrial cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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15 pages, 330 KiB

Open AccessReview

The Role of Methylation of Host and/or Human Papillomavirus (HPV) DNA in Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) Lesions

by Andraž Dovnik and Mario Poljak

Int. J. Mol. Sci. 2023, 24(7), 6479; https://doi.org/10.3390/ijms24076479 - 30 Mar 2023

Cited by 12 | Viewed by 3636

Abstract

Cervical intraepithelial neoplasia grade 2 (CIN2) is an intermediate stage between CIN 1, which is a low-grade lesion, and CIN3, which is the immediate precursor of cervical cancer (CC). Traditionally, CIN2 was regarded as a high-grade lesion and was treated with conization or ablative methods. In recent years, there has been a shift in the management of younger patients, who are now more often being managed conservatively due to frequent spontaneous CIN2 regression and possible adverse effects of treatment on future pregnancies. Because the risk of progression to CC still exists with conservative management, a personalized approach is needed to identify patients with a higher probability of progression. In this regard, research has focused on the role of host and human papillomavirus (HPV) gene methylation. This systematic review summarizes the current knowledge regarding conservative CIN2 management focusing on the main methylation markers and its implementation in conservative CIN2 management, and it describes major ongoing longitudinal studies on the subject. The review showed that DNA methylation is an accurate predictor of disease progression and a valid triage tool for HPV-positive women, with CIN2 performing better than triage cytology. Because virtually all CCs are methylation-positive, methylation-negative women at baseline have an extremely low risk of CC. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

10 pages, 252 KiB

Open AccessReview

Ovarian Cancer and Glutamine Metabolism

by Zacharias Fasoulakis, Antonios Koutras, Thomas Ntounis, Ioannis Prokopakis, Paraskevas Perros, Athanasios Chionis, Ioakeim Sapantzoglou, Alexandros Katrachouras, Kyriakos Konis, Athina A. Samara, Asimina Valsamaki, Vasileios-Chrysovalantis Palios, Panagiotis Symeonidis, Konstantinos Nikolettos, Athanasios Pagkalos, Sotirios Sotiriou, Marianna Theodora, Panos Antsaklis, Georgios Daskalakis and Emmanuel N. Kontomanolis

Int. J. Mol. Sci. 2023, 24(5), 5041; https://doi.org/10.3390/ijms24055041 - 6 Mar 2023

Cited by 12 | Viewed by 3188

Abstract

Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there is a link between glutamine metabolism and the proliferation of cancer cells, demonstrating that glutamine metabolism is a vital mechanism for all cellular processes, including the development of cancer. Detailed knowledge regarding its degree of engagement in numerous biological processes across distinct cancer types is still lacking, despite the fact that such knowledge is necessary for comprehending the differentiating characteristics of many forms of cancer. This review aims to examine data on glutamine metabolism and ovarian cancer and identify possible therapeutic targets for ovarian cancer treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

15 pages, 1303 KiB

Open AccessReview

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers

by Pei-Qi Lim, I-Hung Han, Kok-Min Seow and Kuo-Hu Chen

Int. J. Mol. Sci. 2022, 23(17), 10078; https://doi.org/10.3390/ijms231710078 - 3 Sep 2022

Cited by 7 | Viewed by 3099

Abstract

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III–IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal–plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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19 pages, 1509 KiB

Open AccessReview

The Molecular Mechanisms of Actions, Effects, and Clinical Implications of PARP Inhibitors in Epithelial Ovarian Cancers: A Systematic Review

by Chien-Hui Lau, Kok-Min Seow and Kuo-Hu Chen

Int. J. Mol. Sci. 2022, 23(15), 8125; https://doi.org/10.3390/ijms23158125 - 23 Jul 2022

Cited by 22 | Viewed by 6265

Abstract

Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or more of the defects in DNA repair pathways, particularly in homologous recombination (HR), which is strictly linked to mutations in breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2). The treatment of ovarian cancer remains a challenge, and the majority of patients with advanced-stage ovarian cancers experience relapse and require additional treatment despite initial therapy, including optimal cytoreductive surgery (CRS) and platinum-based chemotherapy. Targeted therapy at DNA repair genes has become a unique strategy to combat homologous recombination-deficient (HRD) cancers in recent years. Poly (ADP-ribose) polymerase (PARP), a family of proteins, plays an important role in DNA damage repair, genome stability, and apoptosis of cancer cells, especially in HRD cancers. PARP inhibitors (PARPi) have been reported to be highly effective and low-toxicity drugs that will tremendously benefit patients with HRD (i.e., BRCA 1/2 mutated) epithelial ovarian cancer (EOC) by blocking the DNA repair pathways and inducing apoptosis of cancer cells. PARP inhibitors compete with NAD⁺ at the catalytic domain (CAT) of PARP to block PARP catalytic activity and the formation of PAR polymers. These effects compromise the cellular ability to overcome DNA SSB damage. The process of HR, an essential error-free pathway to repair DNA DSBs during cell replication, will be blocked in the condition of BRCA 1/2 mutations. The PARP-associated HR pathway can also be partially interrupted by using PARP inhibitors. Grossly, PARP inhibitors have demonstrated some therapeutic benefits in many randomized phase II and III trials when combined with the standard CRS for advanced EOCs. However, similar to other chemotherapy agents, PARP inhibitors have different clinical indications and toxicity profiles and also face drug resistance, which has become a major challenge. In high-grade epithelial ovarian cancers, the cancer cells under hypoxia- or drug-induced stress have the capacity to become polyploidy giant cancer cells (PGCCs), which can survive the attack of chemotherapeutic agents and start endoreplication. These stem-like, self-renewing PGCCs generate mutations to alter the expression/function of kinases, p53, and stem cell markers, and diploid daughter cells can exhibit drug resistance and facilitate tumor growth and metastasis. In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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13 pages, 1028 KiB

Open AccessReview

The Utilization of Bevacizumab in Patients with Advanced Ovarian Cancer: A Systematic Review of the Mechanisms and Effects

by Chih-Lin Mao, Kok-Min Seow and Kuo-Hu Chen

Int. J. Mol. Sci. 2022, 23(13), 6911; https://doi.org/10.3390/ijms23136911 - 21 Jun 2022

Cited by 21 | Viewed by 5773

Abstract

Most ovarian cancer cases are diagnosed at an advanced stage (III or IV), in which a primary debulking surgery combined with adjuvant systemic chemotherapy is the standard management. Since targeted therapy is less toxic to human cells than systemic chemotherapy, it has drawn much attention and become more popular. Angiogenesis is a critical process during the proliferation of ovarian cancer cells. Currently, many studies have put emphases on anti-angiogenetic medication, such as bevacizumab, the first and most investigated angiogenesis inhibitor that can exert anti-neoplastic effects. Bevacizumab is a recombinant humanized monoclonal antibody that has been approved for first-line maintenance treatment of advanced ovarian cancer. This review is a summary of current literature about the molecular mechanisms of actions, safety, and effects of bevacizumab for use in advanced epithelial ovarian cancer. Some common side effects of bevacizumab will be also discussed. As an inhibitor of angiogenesis, bevacizumab binds to circulating vascular endothelial growth factor (VEGF) and thereby inhibits the binding of VEGF to its receptors on the surface of endothelial cells. Neutralization of VEGF prevents neovascularization and leads to apoptosis of tumor endothelial cells and a decrease in interstitial fluid pressure within the tumors, which allows greater capacity for chemotherapeutic drugs to reach specific targeted sites. Grossly, bevacizumab has demonstrated some significant therapeutic benefits in many randomized trials in combination with the standard chemotherapy for advanced epithelial ovarian cancer. Based on the available evidence, a higher dosage and a longer duration of bevacizumab appear to achieve better therapeutic effects and progression-free survival. On the other hand, patients with more severe diseases or at a higher risk of progression seem to benefit more from bevacizumab use. However, many unknown aspects of bevacizumab, including detailed mechanisms of actions, effectiveness, and safety for the treatment of ovarian cancer, warrant further investigation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

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