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New Insights into the Pathophysiology of Gynecological Cancers

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 36332

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Special Issue Editor

Dr. Rául Goḿez

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Guest Editor

Research Unit on Women’s Health-Institute of Health Research, INCLIVA, 46010 Valencia, Spain
Interests: endometrial cancer, endometriosis, animal models, immunotherapy, RANK, angiogenesis, fertility, pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endometrial and ovarian tumours are the most preponderant and deadliest gynaecological cancers. Classical chemo and radio therapeutic approaches are hampered by toxicity and show limited efficacy especially at advanced disease stage. In this scenario identification of key targets and development of new therapies are on demand. This special issue is open to studies aimed at 1) Identification/Description of new relevant pathways in the onset and progression of the disease 2) Assessing the potential therapeutic effects of alternative approaches by functional experimentation in disease models

1) Identification/Description of new pathways/targets is expected to include in-vitro experiments for identification of novel targets for treatment and/or characterization of novel pathways involved in the onset and/or progression of any ovarian/endometrial cancer subtype. For example, a better knowledge of pathways transduced by oncogenes (K-ras, P53, etc) might identify alternative targets for subsequent intervention and thus overcome classical limitations in targeting oncogenes. Since IJMS is a journal of molecular science, pure clinical studies are not suitable unless combined with biomolecular analysis. In this regard exploratory studies identifying overexpressed/downregulated potential targets in clinical samples might be covered by this issue as long as a) expression is described at the mRNA and protein level simultaneously and b) analysis extends over different types/subtypes of either endometrial or ovarian cancer so as to identify master regulators of diseases progression.
2) Evaluation of therapeutic potential of alternative approaches is expected to include “functional experimentation” in “preclinical models” of endometrial and ovarian cancer. “Preclinical” refers to studies in homologous or heterologous animal models of disease and also in in-vitro models with special interest in those using organoids as the subject of experimentation,. The term “functional experimentation” includes any kind of pharmacological or biological intervention, where the effects of alternative (other than chemotherapy) therapies are assayed. Interventions of interest in the models covered by the topic are exemplified (but not limited) by immunotherapy, vaccines, , nanoparticles or CAR-T therapies.

Dr. Rául Goḿez
Guest Editor

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Keywords

endometrial cancer
ovarian cancer
immunotherapy
new targets
animal models
humanized mouse models
organoids
nanoparticles
CAR-T
oncogenes

Published Papers (11 papers)

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Research

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15 pages, 4029 KiB

Open AccessArticle

BHLHE22 Expression Is Associated with a Proinflammatory Immune Microenvironment and Confers a Favorable Prognosis in Endometrial Cancer

by Darmawi, Lin-Yu Chen, Po-Hsuan Su, Phui-Ly Liew, Hui-Chen Wang, Yu-Chun Weng, Rui-Lan Huang and Hung-Cheng Lai

Int. J. Mol. Sci. 2022, 23(13), 7158; https://doi.org/10.3390/ijms23137158 - 28 Jun 2022

Cited by 2 | Viewed by 1937

Abstract

Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10–20% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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11 pages, 18074 KiB

Open AccessArticle

Ovulation Enhances Intraperitoneal and Ovarian Seedings of High-Grade Serous Carcinoma Cells Originating from the Fallopian Tube: Confirmation in a Bursa-Free Mouse Xenograft Model

by Che-Fang Hsu, Vaishnavi Seenan, Liang-Yuan Wang and Tang-Yuan Chu

Int. J. Mol. Sci. 2022, 23(11), 6211; https://doi.org/10.3390/ijms23116211 - 01 Jun 2022

Cited by 2 | Viewed by 1965

Abstract

Background: Recently, new paradigms for the etiology and origin of ovarian high-grade serous carcinoma (HGSC) have emerged. The carcinogens released during ovulation transform fallopian tube epithelial cells, exfoliating and metastasizing to the peritoneal organs, including the ovaries. Solid in vivo evidence of the paradigms in a mouse model is urgently needed but is hampered by the differing tubo-ovarian structures. In mice, there is a bursa structure surrounding the distal oviduct and ovary. This, on one hand, prevents the direct influence of ovulatory follicular fluid (FF) on the exfoliated tumor cells. On the other hand, it hinders the seeding of exfoliated tumor cells into the ovary. Methods: In this study, we created a bursa-free mouse xenograft model to examine the effect of superovulation on peritoneal and ovarian metastases of transformed human tubal epithelial cells after intraperitoneal injection in NSG mice. Results: The bursa-free mouse model showed a better effect of ovulation on peritoneal metastasis. In this model, superovulation increased the number of transformed human tubal epithelial cell seedlings after intraperitoneal injection. Compared to the bursa-intact state, bursa-free ovaries were more vulnerable to external tumor seeding in either normal ovulation or superovulation state. Conclusions: This study provides the first in vivo evidence that intraperitoneal spreading of tubal HGSC cells is enhanced by ovulation. This study also demonstrated a mouse model for studying ovary-peritoneum interaction in cancer development. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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15 pages, 3733 KiB

Open AccessArticle

Histological Grade and Tumor Stage Are Correlated with Expression of Receptor Activator of Nuclear Factor Kappa b (Rank) in Epithelial Ovarian Cancers

by Raul Gomez, Miguel Á. Tejada, Víctor Rodríguez-García, Octavio Burgués, Ana I. Santos-Llamas, Andrea Martínez-Massa, Antonio Marín-Montes, Juan J. Tarín and Antonio Cano

Int. J. Mol. Sci. 2022, 23(3), 1742; https://doi.org/10.3390/ijms23031742 - 03 Feb 2022

Viewed by 1615

Abstract

The receptor activator of nuclear factor kappa B (RANK) is becoming recognized as a master regulator of tumorigenesis, yet its role in gynecological cancers remains mostly unexplored. We investigated whether there is a gradation of RANK protein and mRNA expression in epithelial ovarian cancer (EOC) according to malignancy and tumor staging. Immunohistochemical expression of RANK was examined in a cohort of 135 (benign n = 29, borderline n= 23 and malignant n = 83) EOCs. Wild type and truncated RANK mRNA isoform quantification was performed in a cohort of 168 (benign n = 26, borderline n = 13 and malignant n = 129) EOCs. RANK protein and mRNA values were increased in malignant vs. benign or borderline conditions across serous, mucinous and endometrioid cancer subtypes. Additionally, a trend of increased RANK values with staging was observed for the mucinous and serous histotype. Thus, increased expression of RANK appears associated with the evolution of disease to the onset of malignancy in EOC. Moreover, in some EOC histotypes, RANK expression is additionally associated with clinicopathological markers of tumor aggressiveness, suggesting a role in further progression of tumor activity. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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37 pages, 7934 KiB

Open AccessArticle

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

by Robert J. Rabelo-Fernández, Ginette S. Santiago-Sánchez, Rohit K. Sharma, Abiel Roche-Lima, Kelvin Carrasquillo Carrion, Ricardo A. Noriega Rivera, Blanca I. Quiñones-Díaz, Swetha Rajasekaran, Jalal Siddiqui, Wayne Miles, Yasmarie Santana Rivera, Fatima Valiyeva and Pablo E. Vivas-Mejia

Int. J. Mol. Sci. 2022, 23(1), 535; https://doi.org/10.3390/ijms23010535 - 04 Jan 2022

Cited by 5 | Viewed by 4149

Abstract

Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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15 pages, 3313 KiB

Open AccessArticle

Host Mesothelin Expression Increases Ovarian Cancer Metastasis in the Peritoneal Microenvironment

by Tyvette S. Hilliard, Brooke Kowalski, Kyle Iwamoto, Elizabeth A. Agadi, Yueying Liu, Jing Yang, Marwa Asem, Yuliya Klymenko, Jeff Johnson, Zonggao Shi, Gifty Marfowaa, Madeleine G. Yemc, Phillip Petrasko and M. Sharon Stack

Int. J. Mol. Sci. 2021, 22(22), 12443; https://doi.org/10.3390/ijms222212443 - 18 Nov 2021

Cited by 10 | Viewed by 2556

Abstract

Mesothelin (MSLN), a glycoprotein normally expressed by mesothelial cells, is overexpressed in ovarian cancer (OvCa) suggesting a role in tumor progression, although the biological function is not fully understood. OvCa has a high mortality rate due to diagnosis at advanced stage disease with intraperitoneal metastasis. Tumor cells detach from the primary tumor as single cells or multicellular aggregates (MCAs) and attach to the mesothelium of organs within the peritoneal cavity producing widely disseminated secondary lesions. To investigate the role of host MSLN in the peritoneal cavity we used a mouse model with a null mutation in the MSLN gene (MSLN^KO). The deletion of host MSLN expression modified the peritoneal ultrastructure resulting in abnormal mesothelial cell surface architecture and altered omental collagen fibril organization. Co-culture of murine OvCa cells with primary mesothelial cells regardless of MSLN expression formed compact MCAs. However, co-culture with MSLN^KO mesothelial cells resulted in smaller MCAs. An allograft tumor study, using wild-type mice (MSLN^WT) or MSLN^KO mice injected intraperitoneally with murine OvCa cells demonstrated a significant decrease in peritoneal metastatic tumor burden in MSLN^KO mice compared to MSLN^WT mice. Together, these data support a role for host MSLN in the progression of OvCa metastasis. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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15 pages, 4501 KiB

Open AccessArticle

Hinokitiol Exhibits Antitumor Properties through Induction of ROS-Mediated Apoptosis and p53-Driven Cell-Cycle Arrest in Endometrial Cancer Cell Lines (Ishikawa, HEC-1A, KLE)

by Hsin-Yuan Chen, Wen-Pin Cheng, Yi-Fen Chiang, Yong-Han Hong, Mohamed Ali, Tsui-Chin Huang, Kai-Lee Wang, Tzong-Ming Shieh, Hsin-Yi Chang and Shih-Min Hsia

Int. J. Mol. Sci. 2021, 22(15), 8268; https://doi.org/10.3390/ijms22158268 - 31 Jul 2021

Cited by 13 | Viewed by 2792

Abstract

Hinokitiol is a natural tropolone derivative that is present in the heartwood of cupressaceous plants, and has been extensively investigated for its anti-inflammatory, antioxidant, and antitumor properties in the context of various diseases. To date, the effects of hinokitiol on endometrial cancer (EC) has not been explored. The purpose of our study was to investigate the anti-proliferative effects of hinokitiol on EC cells. Cell viability was determined with an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the quantification of apoptosis and reactive oxygen species (ROSs) was performed by using flow cytometry, while protein expression was measured with the Western blotting technique. Hinokitiol significantly suppressed cell proliferation through the inhibition of the expression of cell-cycle mediators, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the induction of the tumor suppressor protein p53. In addition, hinokitiol increased the number of apoptotic cells and increased the protein expression of cleaved-poly-ADP-ribose polymerase (PARP) and active cleaved-caspase-3, as well as the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2). Interestingly, except for KLE cells, hinokitiol induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and reducing the sequestosome-1 (p62/SQSTM1) protein level. Furthermore, hinokitiol triggered ROS production and upregulated the phosphorylation of extracellular-signal-regulated kinase (p-ERK1/2) in EC cells. These results demonstrate that hinokitiol has potential anti-proliferative and pro-apoptotic benefits in the treatment of endometrial cancer cell lines (Ishikawa, HEC-1A, and KLE). Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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Review

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30 pages, 1594 KiB

Open AccessReview

The Proteolytic Landscape of Ovarian Cancer: Applications in Nanomedicine

by Cailin O’Connell, Sabrina VandenHeuvel, Aparna Kamat, Shreya Raghavan and Biana Godin

Int. J. Mol. Sci. 2022, 23(17), 9981; https://doi.org/10.3390/ijms23179981 - 01 Sep 2022

Cited by 3 | Viewed by 2416

Abstract

Ovarian cancer (OvCa) is one of the leading causes of mortality globally with an overall 5-year survival of 47%. The predominant subtype of OvCa is epithelial carcinoma, which can be highly aggressive. This review launches with a summary of the clinical features of OvCa, including staging and current techniques for diagnosis and therapy. Further, the important role of proteases in OvCa progression and dissemination is described. Proteases contribute to tumor angiogenesis, remodeling of extracellular matrix, migration and invasion, major processes in OvCa pathology. Multiple proteases, such as metalloproteinases, trypsin, cathepsin and others, are overexpressed in the tumor tissue. Presence of these catabolic enzymes in OvCa tissue can be exploited for improving early diagnosis and therapeutic options in advanced cases. Nanomedicine, being on the interface of molecular and cellular scales, can be designed to be activated by proteases in the OvCa microenvironment. Various types of protease-enabled nanomedicines are described and the studies that focus on their diagnostic, therapeutic and theranostic potential are reviewed. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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16 pages, 1180 KiB

Open AccessReview

The Interplay between PARP Inhibitors and Immunotherapy in Ovarian Cancer: The Rationale behind a New Combination Therapy

by Brigida Anna Maiorano, Domenica Lorusso, Mauro Francesco Pio Maiorano, Davide Ciardiello, Paola Parrella, Antonio Petracca, Gennaro Cormio and Evaristo Maiello

Int. J. Mol. Sci. 2022, 23(7), 3871; https://doi.org/10.3390/ijms23073871 - 31 Mar 2022

Cited by 16 | Viewed by 4139

Abstract

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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13 pages, 656 KiB

Open AccessReview

Rare Subtype of Endometrial Cancer: Undifferentiated/Dedifferentiated Endometrial Carcinoma, from Genetic Aspects to Clinical Practice

by Hsiu-Jung Tung, Ren-Chin Wu, Chiao-Yun Lin and Chyong-Huey Lai

Int. J. Mol. Sci. 2022, 23(7), 3794; https://doi.org/10.3390/ijms23073794 - 30 Mar 2022

Cited by 8 | Viewed by 3127

Abstract

Endometrial cancer (EC) is one of the most common gynecologic cancers worldwide. There were 417,367 newly diagnosed cases and 97,370 deaths due to this disease worldwide in 2020. The incidence rates have increased over time, especially in countries with rapid socioeconomic transitions, and EC has been the most prevalent gynecologic malignancy in Taiwan since 2012. The new EC molecular classifications of The Cancer Genome Atlas (TCGA) Research Network include clear-cell carcinoma, serous carcinoma, and carcinosarcoma, while undifferentiated/dedifferentiated EC (UDEC) is not mentioned, and most previous clinical trials for EC have not included UDEC. UDEC is rare, has an aggressive growth pattern, tends to be diagnosed at an advanced stage, and is resistant to conventional chemotherapy. In this review, case series or case reports on the clinical features and genomic/epigenetic and expression profiles on UDEC data are summarized in order to identify potential molecular targets for current and future research. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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30 pages, 2813 KiB

Open AccessReview

Human Papillomaviruses as Infectious Agents in Gynecological Cancers. Oncogenic Properties of Viral Proteins

by Daria A. Haręża, Jacek R. Wilczyński and Edyta Paradowska

Int. J. Mol. Sci. 2022, 23(3), 1818; https://doi.org/10.3390/ijms23031818 - 05 Feb 2022

Cited by 31 | Viewed by 7426

Abstract

Human papillomaviruses (HPVs), which belong to the Papillomaviridae family, constitute a group of small nonenveloped double-stranded DNA viruses. HPV has a small genome that only encodes a few proteins, and it is also responsible for 5% of all human cancers, including cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV types may be classified as high- and low-risk genotypes (HR-HPVs and LR-HPVs, respectively) according to their oncogenic potential. HR-HPV 16 and 18 are the most common types worldwide and are the primary types that are responsible for most HPV-related cancers. The activity of the viral E6 and E7 oncoproteins, which interfere with critical cell cycle points such as suppressive tumor protein p53 (p53) and retinoblastoma protein (pRB), is the major contributor to HPV-induced neoplastic initiation and progression of carcinogenesis. In addition, the E5 protein might also play a significant role in tumorigenesis. The role of HPV in the pathogenesis of gynecological cancers is still not fully understood, which indicates a wide spectrum of potential research areas. This review focuses on HPV biology, the distribution of HPVs in gynecological cancers, the properties of viral oncoproteins, and the molecular mechanisms of carcinogenesis. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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22 pages, 1565 KiB

Open AccessReview

The Important Role of Ion Transport System in Cervical Cancer

by Yih-Fung Chen and Meng-Ru Shen

Int. J. Mol. Sci. 2022, 23(1), 333; https://doi.org/10.3390/ijms23010333 - 29 Dec 2021

Cited by 2 | Viewed by 2661

Abstract

Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca²⁺ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl⁻ channels and K⁺-Cl⁻ cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca²⁺ homeostasis, the Ca²⁺ store sensor STIM molecules and plasma membrane Ca²⁺ channel Orai proteins, the predominant Ca²⁺ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges. Full article

(This article belongs to the Special Issue New Insights into the Pathophysiology of Gynecological Cancers)

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