Background: Incessant ovulation is the main etiologic factor of ovarian high-grade serous carcinomas (HGSC), which mostly originate from the fallopian tube epithelium (FTE). Receptor tyrosine kinase (RTK) ligands essential for follicle development and ovulation wound repair were abundant in the follicular fluid (FF) and promoted the transformation of FTE cells. This study determined whether RTK ligands are present in FF exosomes and whether epidermal growth factor receptor (EGFR) signaling is essential for oncogenic activity.
Methods: The FF of women undergoing in vitro fertilization was fractionated based on the richness of exosomes and tested for transformation toward FTE cells under different RTK inhibitors. EGFR ligands in FF exosomes were identified, and downstream signaling proteins in FTE cells were characterized.
Results: The transforming activity of FF was almost exclusively enriched in exosomes, which possess a high capacity to induce anchorage-independent growth, clonogenicity, migration, invasion, and proliferation of FTE cells. EGFR inhibition abolished most of these activities. FF and FF exosome exposure markedly increased EGFR phosphorylation and the downstream signal proteins, including AKT, MAPK, and FAK. Multiple EGF family growth factors, such as amphiregulin, epiregulin, betacellulin, and transforming growth factor-alpha, were identified in FF exosomes.
Conclusions: Our results demonstrate that FF exosomes serve as carriers of EGFR ligands as well as ligands of other RTKs that mediate the transformation of FTE cells and underscore the need to further explore the content and roles of FF exosomes in HGSC development.
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http://dx.doi.org/10.1186/s12935-024-03614-9 | DOI Listing |
Cancer Cell Int
December 2024
Center for Prevention and Therapy of Gynecological Cancers, Department of Research, Hualien, 970, Taiwan, ROC.
Neoplasia
January 2025
Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, ROC; Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC. Electronic address:
Introduction: 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.
View Article and Find Full Text PDFbioRxiv
October 2024
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, 95064.
Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentum and peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread.
View Article and Find Full Text PDFSci Rep
October 2024
Radioisotopes Department, Nuclear Research Centre, Egyptian Atomic Energy Authority, Cairo, Egypt.
This study explores the impact of γ-irradiation on ethanolic extracts of Solanum aculeastrum Dunal. The anti-cancer and antimicrobial properties were investigated. The obtained results revealed that total phenol (TP) and total flavonoid (TF) of total ethanol extract (100%) (FTE) were higher than 70% ethanol extract (SE), and these contents increased after gamma radiation with 5 kGy.
View Article and Find Full Text PDFNutrients
September 2024
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Endeavor Health, Evanston, IL 60201, USA.
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