Dah-Ching Ding

Role of Leucine-Rich Repeat–Containing G-Protein-Coupled Receptors 4–6 (LGR4–6) in the Ovary and Other Female Reproductive Organs: A Literature Review

Leucine-rich repeat–containing G-protein-coupled receptors regulate stem cell activity and tissue homeostasis within female reproductive organs, primarily through their interaction with the Wnt/β-catenin signaling pathway. LGR4–6 are increasingly recognized for their roles in organ development, regeneration, and cancer. This review aims to provide a comprehensive overview of the roles of LGR4–6 in female reproductive organs, highlighting their significance in normal physiology and disease states, specifically in the context of ovarian cancer. LGR4 is essential for the proper development of the female reproductive system; its deficiency leads to significant reproductive abnormalities, including delayed menarche and follicle development issues. LGR5 is a well-established marker of stem cells in the ovary and fallopian tubes. It has been implicated in the pathogenesis of high-grade serous ovarian cancer. LGR6, while less studied, shares functional similarities with LGR5 and can maintain stemness. It contributes to chemoresistance in ovarian cancer. LGR6 is a marker for fallopian tube stem cells and is involved in stem cell maintenance and differentiation. LGR4–6 regulate the pathophysiology of female reproductive tissues. LGR4–6 are promising therapeutic targets for treating reproductive cancers and other related disorders. Molecular mechanisms underlying the functions of LGR4–6 should be studied.

Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium

Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination. The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined. FF induced AID activation and de novo FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the TP53 gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC. This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial TP53 mutation and invited a strategy of antioxidation in prevention of HGSC.

Endometrial Cancer-Infiltrating Mesenchymal Stem Cells Exhibit Immunosuppressive Effects

Endometrial cancer is the most common gynecologic cancer with high heterogeneity. However, there are limited treatment options for advanced endometrial carcinoma. In recent years, immunotherapy has broadly been used for the treatment of various cancers. However, the efficacy of immunotherapy against endometrial cancer is limited. The tumor microenvironment, including mesenchymal stem cells (MSCs), may contribute to tumor progression through cancer cells themselves and through cells of the immune system. We successfully isolated endometrial cancer–derived MSCs (EmCaMSCs) from patients and found that the population of MSCs in tumor tissues was approximately 1%–5%. The population of MSCs correlated with the stage of the disease. EmCaMSCs expressed MSC markers and exhibited trilineage differentiation ability. The programmed death ligands PD-L1 and PD-L2 were highly expressed in EmCaMSCs; their expression could be further enhanced by tumor necrosis factor-α and interferon-γ. When cocultured with peripheral blood mononuclear cells (PBMCs), anti-CD3, and anti-CD28, EmCaMSCs inhibited the proliferation of PBMCs, which were partially rescued by treatment with anti-PD-L1 antibodies. From the profile of conditioned medium of EmCaMSCs, we discovered that interleukin (IL)-8 and insulin-like growth factor–binding protein 6 could also rescue the proliferation of PBMCs. Furthermore, EmCaMSCs cocultured with IL-2-induced PBMCs exhibited decreased expression of CD56, CD4, and CD8 and showed decreased cytotoxicity toward K562 cells and endometrial cancer cells. Overall, EmCaMSCs were isolated successfully from endometrial cancer tissues and exhibited immunosuppressive effects and may be targeted for the treatment of endometrial cancer by anti-cytokine and immune checkpoint inhibitors. The percentage of MSCs in tumor stroma might predict the prognosis of endometrial cancer.

A clear cancer cell line (150057) derived from human endometrial carcinoma harbors two novel mutations

Abstract Background Cell lines are extremely useful for both basic and clinical research. Thus, establishing endometrial cancer cell lines with malignant histology is important. This study aimed to extensively characterize an endometrial clear cell carcinoma cell line. Methods This cell line, named 150,057, was derived from the endometrial clear cell cancer of a 63-year-old woman. The morphology, chromosomes, chemosensitivity, tumor markers, xenotransplantation characteristics, and cancer-related genes of the cell line were characterized. Results This cell line exhibited adequate growth, being passaged more than 70 times. The morphology of the cells was polygonal with a cobblestone-like appearance. Karyotyping of the cell line revealed a hypodiploid chromosomal number. 150057 cells expressed CA19–9 and CA125. The cell line was sensitive to doxorubicin, paclitaxel, carboplatin, and cisplatin. After the cells were transplanted into the subcutaneous region of non-obese diabetic-severe combined immunodeficiency mice, they generated xenograft tumors with similar histology as the original tumor. A total of 59 somatic nucleotide mutations were identified in 25 of the 53 examined tumor suppressor genes and oncogenes. Two novel mutations were found in FGFR3 and ARID1A. Conclusion We established and characterized an endometrial clear cell carcinoma cell line that may be useful in carcinogenesis and treatment research for endometrial cancer.

Ovarian Cancer Patient-Derived Organoids Used as a Model for Replicating Genetic Characteristics and Testing Drug Responsiveness: A Preliminary Study

This study aimed to explore the role of ovarian cancer patient-derived organoids (PDOs) in their replicating genetic characteristics and testing drug responsiveness. Ovarian cancer PDOs were cultured in Matrigel with a specialized medium. The successful rate and proliferation rate were calculated. Morphology, histology, and immunohistochemistry (IHC) (PAX8, P53, and WT1) were used to identify the tumor characteristics. Gene sequencing, variant allele frequency (VAF), and copy number variation were used to explore the mutation profile. The sensitivity to chemodrugs (carboplatin, paclitaxel, gemcitabine, doxorubicin, and olaparib) was conducted. Successful generation of organoids occurred in 54% (7/13) of attempts, encompassing 4 high-grade serous carcinomas (HGSC), 1 mucinous carcinoma (MC), 1 clear cell carcinoma (CCC), and 1 carcinosarcoma. The experiments used six organoids (3 HGSC, 1 CCC, 1 MC, and 1 carcinosarcoma). The derived organoids exhibited spherical-like morphology, and the diameter ranged from 100 to 500 μm. The histology and IHC exhibited the same between organoids and primary tumors. After cryopreservation, the organoid’s growth rate was slower than the primary culture (14 days vs 10 days, P < 0.01). Targeted sequencing revealed shared DNA variants, including mutations in key genes, such as BRCA1, PIK3CA, ARID1A, and TP53. VAF was similar between primary tumors and organoids. The organoids maintained inherited most copy number alterations. Drug sensitivity testing revealed varying responses, with carcinosarcoma organoids showing higher sensitivity to paclitaxel and gemcitabine than HGSC organoids. Our preliminary results showed that ovarian cancer PDOs could be successfully derived and histology, mutations, and diverse copy numbers of genotypes could be faithfully captured. Drug testing could reveal the individual PDO’s responsiveness to drugs. PDOs might be as valuable resources for investigating genomic biomarkers for personalized treatment.

Bone Marrow Mesenchymal Stem Cells Promote Ovarian Cancer Cell Proliferation via Cytokine Interactions

Bone marrow mesenchymal stem cells (BMSCs) are key players in promoting ovarian cancer cell proliferation, orchestrated by the dynamic interplay between cytokines and their interactions with immune cells; however, the intricate crosstalk among BMSCs and cytokines has not yet been elucidated. Here, we aimed to investigate interactions between BMSCs and ovarian cancer cells. We established BMSCs with a characterized morphology, surface marker expression, and tri-lineage differentiation potential. Ovarian cancer cells (SKOV3) cultured with conditioned medium from BMSCs showed increased migration, invasion, and colony formation, indicating the role of the tumor microenvironment in influencing cancer cell behavior. BMSCs promoted SKOV3 tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice, increasing tumor growth. The co-injection of BMSCs increased the phosphorylation of p38 MAPK and GSK-3β in SKOV3 tumors. Co-culturing SKOV3 cells with BMSCs led to an increase in the expression of cytokines, especially MCP-1 and IL-6. These findings highlight the influence of BMSCs on ovarian cancer cell behavior and the potential involvement of specific cytokines in mediating these effects. Understanding these mechanisms will highlight potential therapeutic avenues that may halt ovarian cancer progression.

Spontaneous Transformation of a p53 and Rb-Defective Human Fallopian Tube Epithelial Cell Line after Long Passage with Features of High-Grade Serous Carcinoma

Ovarian cancer is one of the most lethal gynecological cancers, and 80% are high-grade serous carcinomas (HGSOC). Despite advances in chemotherapy and the development of targeted therapies, the survival rate of HGSOC has only moderately improved. Therefore, a cell model that reflects the pathogenesis and clinical characteristics of this disease is urgently needed. We previously developed a human fallopian tube epithelial cell line (FE25) with p53 and Rb deficiencies. After long-term culture in vitro, cells at high-passage numbers showed spontaneous transformation (FE25L). This study aimed to compare FE25 cells cultured in vitro for low (passage 16–31) and high passages (passage 116–139) to determine whether these cells can serve as an ideal cell model of HGSOC. Compared to the cells at low passage, FE25L cells showed increased cell proliferation, clonogenicity, polyploidy, aneuploidy, cell migration, and invasion. They also showed more resistance to chemotherapy and the ability to grow tumors in xenografts. RNA-seq data also showed upregulation of hypoxia, epithelial-mesenchymal transition (EMT), and the NF-κB pathway in FE25L compared to FE25 cells. qRT-PCR confirmed the upregulation of EMT, cytokines, NF-κB, c-Myc, and the Wnt/β-catenin pathway. Cross-platform comparability found that FE25L cells could be grouped with the other most likely HGSOC lines, such as TYKNU and COV362. In conclusion, FE25L cells showed more aggressive malignant behavior than FE25 cells and hence might serve as a more suitable model for HGSOC research.

Ovarian remnant syndrome with paraintestinal ovarian serous cystadenofibroma arose 30 years after bilateral salpingo-oophorectomy: A case report

Rationale: Ovarian cystadenofibroma is a relatively rare benign ovarian tumor. Ovarian remnant syndrome (ORS) is a rare complication of bilateral salpingo-oophorectomy (BSO). We report a rare case of ORS with paraintestinal ovarian serous cystadenofibroma that developed 30 years after total abdominal hysterectomy and BSO in a 73-year-old woman. Patient concerns: A 73-year-old woman complained of long-term lower abdominal discomfort. Diagnosis: She was diagnosed with a cystic lesion in the lower abdomen on transabdominal ultrasonography. Further diagnostic imaging and laboratory tests could not exclude a diagnosis of malignancy. Interventions: The patient underwent laparoendoscopic single-site surgery. We found one cystic lesion 5 cm in size with multiple septa that was adhered to the small bowel. We consulted a general surgeon for tumor resection. Dissection was performed and the specimen was then removed from the umbilical wound. Outcomes: Histopathological examination revealed an ovarian serous cystadenofibroma. The postoperative recovery was uneventful. Lessons: Patients with lower abdominal pain after a previous hysterectomy and BSO should be examined with transabdominal sonography for ORS.

Possible Association of Hysterectomy Accompanied with Opportunistic Salpingectomy with Early Menopause: A Retrospective Cohort Study

Opportunistic salpingectomies (OSs) are concurrently performed with hysterectomies to prevent epithelial ovarian cancer. This study aimed to investigate the correlation between OS and early menopause in females who have undergone hysterectomies. This was a retrospective cohort study involving 79 females who had undergone a hysterectomy, with or without an OS, between January 2007 and December 2015. Their ages at surgery, at menopause, and the lengths of time from surgery to menopause were compared. An OS had been performed in 54 and not performed in 25 of the enrolled patients, comprising the OS and non-OS groups. Body mass index was significantly higher in the OS group (OS: 25.27 ± 4.17 vs. non-OS: 22.97 ± 3.27, p = 0.01). Additionally, menopausal sleep problems were more prevalent in the OS group than in the non-OS group (41% vs. 12%, p = 0.01). Notably, the time from surgery to menopause was significantly shorter in the OS group than in the non-OS group (OS: 1.84 ± 1.85 vs. non-OS: 2.93 ± 2.43, p = 0.031). After adjusting the covariates, the OS group was associated with a significantly shorter period between surgery and menopause (p = 0.029). In conclusion, these results showed that a hysterectomy plus an OS might cause earlier menopause than a hysterectomy only. An OS should be preoperatively discussed with patients regarding the possibility of early menopause. The findings of this study require further large-scale investigations to reinforce the results.

Condyloma acuminatum mimicking cervical cancer in a pregnant woman and treatment with cryotherapy: A case report

Rationale: Condyloma acuminata and anogenital warts are protruding papillomatous lesions caused by human papillomavirus. In pregnant women, condyloma acuminata over the cervical region may grow rapidly, mimicking cervical cancer. Patient concerns: A pregnant woman at 14 weeks of gestation with condyloma acuminatum mimicking cervical cancer was referred to our hospital for further management. Diagnosis: Condyloma acuminata. Interventions: Tumor biopsy was performed twice, and the pathology confirmed condyloma acuminatum. Immunohistochemistry revealed focal positivity for p16 and Ki-67. Cryotherapy was performed and regular follow-up was performed at 2-week intervals. A small residual condyloma acuminata was found and treated with cryotherapy. Outcome: During the follow-up period, no recurrence of condyloma acuminata was noted. She delivered a baby at 37 weeks of gestation via cesarean section, without complications. Lessons: Condyloma acuminata of the cervix may grow faster during pregnancy, mimicking cervical cancer. Multiple factors must be considered when treating condyloma acuminata during pregnancy. Cryotherapy is proposed as a 1st-line treatment in all trimesters because of its safety, convenience, and cost-effectiveness. Serial follow-up at 2-week intervals to observe post-cryotherapy conditions is recommended.

Adenomyoma recurrence 7 years after laparoscopic supracervical hysterectomy: A case report and literature review

Rationale: Adenomyosis, a gynecological condition characterized by endometrial tissue within the uterine myometrium, often leads to menstrual pain and heavy bleeding, significantly affecting the quality of life. The primary treatment for adenomyosis and leiomyomas is hysterectomy. However, in rare instances, these conditions can recur in the cervical stump following a hysterectomy. Here, we present a case of cervical adenomyoma development after a prior laparoscopic supracervical hysterectomy. Patient Concerns: A 47-year-old woman sought medical attention due to increased vaginal bleeding. Diagnoses: She had undergone a laparoscopic supracervical hysterectomy 7 years earlier to address uterine myoma and adenomyosis. Just 1 month posthysterectomy, a pelvic ultrasound revealed the presence of a cervical stump measuring approximately 4.0 × 4.0 cm. Subsequent follow-up ultrasounds documented the gradual growth of the cervical mass. Two years ago, a recurrent myoma was identified, and the patient experienced intermittent vaginal bleeding. Over 7 years, the cervical mass increased from 4 to 7 cm. Preadmission pelvic ultrasonography confirmed the existence of cervical adenomyoma measuring 7 × 6 cm. Interventions: Consequently, the patient underwent a laparoscopic trachelectomy. Intraoperatively, an enlarged cervix, approximately 7 × 6 cm in size, containing adenomyoma was observed. A gross examination of the specimen indicated hypertrophic muscle tissue and hemorrhagic foci. Subsequent histopathological examination confirmed the presence of adenomyoma. Outcomes: Remarkably, the patient exhibited no recurrence over the subsequent 8 months. Lessons: The case presented here highlights the potential occurrence of cervical adenomyoma following a supracervical hysterectomy. Management options include hormone therapy and surgical excision. Furthermore, annual follow-up comprising ultrasound and pap smear evaluations is recommended for patients with supracervical hysterectomies to detect and address possible recurrences.

The effect of Jing Si herbal tea on cancer-related fatigue in gynecologic cancer patients: A randomized controlled trial

Background: Cancer-related fatigue (CRF) is a persistent, distressing, subjective sense of physical, emotional, or cognitive tiredness or exhaustion disproportionate to recent activity and interferes with normal functioning. Jing Si herbal tea (JSHT) has shown several pharmacological actions in preclinical and clinical models. We aimed to investigate the effect of JSHT on alleviating CRF in patients with gynecological cancer. Methods: A randomized controlled trial was conducted at our hospital from March 1, 2021 to December 31, 2023. Participants aged 20 to 80 years with gynecologic cancer and moderate-to-severe CRF were randomly categorized into 2 groups. The intervention group was given JSHT twice daily for 6 weeks, while the control group was given a placebo for 3 weeks and JSHT for the following 3 weeks. The primary outcomes were fatigue and quality of life, which were evaluated using the brief fatigue inventory-total (BFI-T) and functional assessment of cancer therapy-general 7 scale. The secondary outcomes included white blood cells and differential counts. Results: Among the 19 participants, there was no significant difference in CRF (BFI-T) and quality of life (functional assessment of cancer therapy-general 7) improvement between the intervention group (n = 9) and the control group (n = 10). However, both groups showed significant improvements in BFI-T: global fatigue score, BFI-T: fatigue intensity, and BFI-T: fatigue interference after treatment ( P  < .05). The difference in monocyte count was statistically significant after treatment in both groups ( P  < .001), with the intervention group showing a significant decrease in monocyte count compared to the control group at the beginning of cycle 2 ( P  < .05). Conclusion: Both intervention and control groups improved fatigue and decreased monocyte counts. Further research is needed to explore these findings and their clinical relevance.