The uterine secretome initiates growth of gynecologic tissues in ectopic locations.

Endosalpingiosis (ES) and endometriosis (EM) refer to the growth of tubal and endometrial epithelium respectively, outside of their site of origin. We hypothesize that uterine secretome factors drive ectopic growth. To test this, we developed a mouse model of ES and EM using tdTomato (tdT) transgenic fluorescent mice as donors. To block implantation factors, progesterone knockout (PKO) tdT mice were created. Fluorescent lesions were present after oviduct implantation with and without WT endometrium. Implantation was increased (p<0.05) when tdt oviductal tissue was implanted with endometrium compared to oviductal tissue alone. Implantation was reduced (p<0.0005) in animals implanted with minced tdT oviductal tissue with PKO tdT endometrium compared to WT endometrium. Finally, oviductal tissues was incubated with and without a known implantation factor, leukemia inhibitory factor (LIF) prior to and during implantation. LIF promoted lesion implantation. In conclusion, endometrial derived implantation factors, such as LIF, are necessary to initiate ectopic tissue growth. We have developed an animal model of ectopic growth of gynecologic tissues in a WT mouse which will potentially allow for development of new prevention and treatment modalities.

Sperm functionality is differentially regulated by porcine oviductal extracellular vesicles from the distinct phases of the estrous cycle.

Context Extracellular vesicles (EVs) derived from the oviductal fluid (oEVs) play a critical role in various reproductive processes, including sperm capacitation, fertilisation, and early embryo development. Aims To characterise porcine oEVs (poEVs) from different stages of the estrous cycle (late follicular, LF; early luteal, EL; mid luteal, ML; late luteal, LL) and investigate their impact on sperm functionality. Methods poEVs were isolated, characterised, and labelled to assess their binding to boar spermatozoa. The effects of poEVs on sperm motility, viability, acrosomal status, protein kinase A phosphorylation (pPKAs), tyrosine phosphorylation (Tyr-P), and in in vitro fertility were analysed. Key results poEVs were observed as round or cup-shaped membrane-surrounded vesicles. Statistical analysis showed that poEVs did not significantly differ in size, quantity, or protein concentration among phases of the estrous cycle. However, LF poEVs demonstrated a higher affinity for binding to sperm. Treatment with EL, ML, and LL poEVs resulted in a decrease in sperm progressive motility and total motility. Moreover, pPKA levels were reduced in presence of LF, EL, and ML poEVs, while Tyr-P levels did not differ between groups. LF poEVs also reduced sperm penetration rate and the number of spermatozoa per penetrated oocyte (P Conclusions poEVs from different stages of the estrous cycle play a modulatory role in sperm functionality by interacting with spermatozoa, affecting motility and capacitation, and participating in sperm-oocyte interaction. Implications The differential effects of LF and LL poEVs suggest the potential use of poEVs as additives in IVF systems to regulate sperm-oocyte interaction.

IL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube.

The human pathogen Neisseria gonorrhoeae ascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes and pelvic inflammatory disease (PID), increasing the risk of infertility and ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use of ex vivo cultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal infection nor pelvic inflammatory disease and thus it was selected for further characterization. We show that human Fallopian tubes express the IL-17C receptor on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.

Paraspeckles / CARM1 mediates the regulation of OEVs on cell differentiation during in vitro embryonic development of yak.

Mammalian embryos produced in vitro have poor embryo quality and low developmental ability compared with in vivo embryos. The main manifestations are the low number of blastocysts, the low ratio of the number of inner cell mass cells to the number of trophoblastic cells, and the high apoptosis rate of blastocysts, resulting in low embryo implantation rate. Therefore, optimizing in vitro culture conditions has become a key technology to im-prove the quality of preimplantation embryos. Oviduct Epithelial cells exosomes (OEVs) can be absorbed and internalized by embryos to improve the blastocyst rate and blastocyst quality of embryos in vitro. As a special nuclear structure, Paraspeckles are involved in the fate determination of mammalian early embryonic mammalian cells. However, the regulation of embryonic cell differentiation by OEVs remains unknown. We aimed to investigate the effects of OEVs on paraspeckle formation and cell fate determination in yak in vitro fertilization (IVF) of em-bryos. To simulate the in vivo oviduct environment after ovulation, we used follicular fluid exosomes (FEVs) to stimulate yak oviduct epithelial cells and collect OEVs. OEVs were added to the yak IVF embryo culture system. Paraspeckle formation, cell differentiation, and blastocyst quality in yak embryos were determined. Our results show that, development of yak embryos is unique compared to other bovine species, and OEVs can be used as a supplement to the in vitro culture system of yak embryos to improve embryonic development and blas-tocyst quality. And also Paraspeckles/CARM1 mediated the regulation of OEVs on cell differentiation during in vitro yak embryo production. These results provide new insights into the study of yak embryonic development and the role of OEVs in embryonic development.

Chronic interstitial ectopic pregnancy presenting with a negative urine pregnancy test.

The ampulla portion of the fallopian tube is the most common site of ectopic pregnancy (70%), with approximately 2% of pregnancies implanted in the interstitial portion. In general, an interstitial ectopic pregnancy (IEP) is difficult to diagnose and is associated with a high rate of complications-most patients with an IEP present with severe abdominal pain and haemorrhagic shock due to an ectopic rupture. Chronic tubal pregnancy (CTP) is an uncommon condition with an incidence of 20%. The CTP has a longer clinical course and a negative or low level of serum beta-human chorionic gonadotropin due to perished chorionic villi. This study presents a case of a woman who was diagnosed with a chronic IEP (CIEP) which was successfully treated by surgery. This case also acts as a cautionary reminder of considering a CIEP in women of reproductive age presenting with amenorrhea, vaginal bleeding and a negative pregnancy test.

Bowel perforation with generalised peritonitis secondary to recurrent primary fallopian tube carcinoma after 17 years.

We describe a case of bowel perforation secondary to a recurrence of primary fallopian tube carcinoma treated more than a decade ago. A woman in her 70s presented to a rural centre with an acute abdomen. An abdominal CT showed a perforated ileum secondary to a pelvic mass. Emergency laparotomy identified the pelvic mass that was adherent to the side wall and invading the ileum at the site of perforation. Its adherence to the external iliac vessels posed a challenge to achieve en-bloc resection; therefore, a defunctioning loop ileostomy was created. Final histopathology and immunopathology were consistent with the recurrence of her primary fallopian tube carcinoma. The patient was further discussed in a multidisciplinary team meeting at a tertiary referral hospital. This case highlighted the importance of having a high index of suspicion for cancer recurrence, the utility of rapid source control laparotomy and multidisciplinary team patient management.

Mechanical properties of native and decellularized reproductive tissues: insights for tissue engineering strategies.

Understanding the mechanical properties and porosity of reproductive tissues is vital for regenerative medicine and tissue engineering. This study investigated the changes in Young's modulus (YM), storage modulus (E'), loss modulus (E"), and porosity of native and decellularized bovine reproductive tissues during the estrous cycle. Testis tunica albuginea had significantly higher YM, E', and E" than the inner testis, indicating greater stiffness and viscoelasticity. Endometrium showed no distinct differences in YM, E', or E" across the estrous cycle or between horns. Ovaries exhibited significant variations in YM, E', E", and porosity, with higher YM and E' in the ipsilateral cortex and medulla during the luteal phase. Decellularized ovarian tissues displayed increased porosity. The oviduct displayed no significant differences in YM or E' in the isthmus, but the contralateral ampulla had reduced YM and E' in the luteal phase. These findings offer valuable insights into the dynamic mechanical properties and porosity of reproductive tissues, facilitating the development of biomimetic scaffolds for tissue engineering applications.

Isolated fallopian tube torsion: A systematic review of case reports.

OBJECTIVE: To combine all literature describing cases of isolated fallopian tube torsion in adult non pregnant patients in a systematic manner, to optimize knowledge and practice both for diagnosis and management. STUDY DESIGN: EMBASE and PubMed databases were searched for the terms 'tubal' OR 'fallopian tube' AND 'isolated' AND 'torsion' from the inception of these databases to July 5, 2023. All case reports or case series of adult patients (18 years or older) with isolated fallopian tube torsion were included. Exclusion criteria included: all other study types; cases involving children and adolescents (less than 18 years old); pregnant patients of all trimesters; tubo-ovarian torsion; studies not published in English; duplicates and those not available in text. Following the database search, two authors independently screened the studies and search results were subsequently reported in accordance with PRISMA guidelines. Data was extracted independently by two authors and analysed using Excel. All cases were assessed for bias using a modified version of the tool proposed by Murad et al. RESULTS: 92 unique articles enrolling 131 individual cases were included in this systematic review. Isolated fallopian tube torsion most commonly occurs during reproductive ages between 18 and 45 years. It is uncommon in postmenopausal women. The most common presenting symptoms include unilateral lower abdominal or pelvic pain along the affected side with nausea and vomiting. Risk factors can be intrinsic or extrinsic and can include conditions such as hydrosalpinx, sterilization, pelvic inflammatory disease or cysts. Ultrasound is the optimal imaging modality however Computed Tomography and Magnetic Resonance Imaging can also be used. Imaging in general has low sensitivity, however isolated fallopian tube torsion can be identified with appropriate expertise. The gold standard for isolated fallopian tube torsion management is laparoscopy and detorsion however currently, the most common intervention performed is salpingectomy. CONCLUSIONS: Isolated fallopian tube torsion is a rare but important gynaecological emergency with significant fertility implications. This study summarizes the most common presentations, investigation findings and surgical interventions in patients with isolated fallopian tube torsion. This study also emphasizes the importance of clinicians maintaining a high degree of suspicion and low threshold for early laparoscopic intervention to retain fertility.

Diagnosis Shift in Site of Origin of Tubo-Ovarian Carcinoma.

OBJECTIVE: To assess population-level trends, characteristics, and outcomes of high-grade serous tubo-ovarian carcinoma in the United States. METHODS: This retrospective cohort study queried the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The study population was 27,811 patients diagnosed with high-grade serous tubo-ovarian carcinoma from 2004 to 2020. The exposure was the primary cancer site (ovary or fallopian tube). Main outcome measures were temporal trends, clinical characteristics, and overall survival associated with primary cancer site assessed in multivariable analysis. RESULTS: The study population comprised 23,967 diagnoses of high-grade serous ovarian carcinoma and 3,844 diagnoses of high-grade serous fallopian tubal carcinoma. The proportion of diagnoses of high-grade serous fallopian tubal carcinoma increased from 365 of 7,305 (5.0%) in 2004-2008 to 1,742 of 6,663 (26.1%) in 2017-2020. This increase was independent in a multivariable analysis (adjusted odds ratio [aOR] vs 2004-2008, 2.28 [95% CI, 1.98-2.62], 3.27 [95% CI, 2.86-3.74], and 6.65 [95% CI, 5.84-7.57] for 2009-2012, 2013-2016, and 2017-2020, respectively). This increase in high-grade serous fallopian tubal carcinoma was seen across age groups (4.3-5.8% to 22.7-28.3%) and across racial and ethnic groups (4.1-6.0% to 21.9-27.5%) (all P for trend <.001). Among the cases of tumors smaller than 1.5 cm, the increase was particularly high (16.9-67.6%, P for trend <.001). Primary-site tumors in the high-grade serous fallopian tubal carcinoma group were more likely to be smaller than 1.5 cm (aOR 8.26, 95% CI, 7.35-9.28) and unilateral (aOR 7.22, 95% CI, 6.54-7.96) compared with those in high-grade serous ovarian carcinoma. At the cohort level, the diagnosis shift to high-grade serous fallopian tubal carcinoma was associated with narrowing differences in survival over time between the two malignancy groups: adjusted hazard ratio 0.84 (95% CI, 0.74-0.96), 0.91 (95% CI, 0.82-1.01), 1.01 (95% CI, 0.92-1.12), and 1.12 (95% CI, 0.98-1.29) for 2004-2008, 2009-2012, 2013-2016, and 2017-2020, respectively. CONCLUSION: This population-based assessment suggests that diagnoses of high-grade serous tubo-ovarian carcinoma in the United States have been rapidly shifting from high-grade serous ovarian to fallopian tubal carcinoma in recent years, particularly in cases of smaller, unilateral tumors.

Oviduct and endometrial epithelium improve in vitro produced bovine embryo developmental kinetics.

In brief: Standard in vitro produced (IVP) bovine embryo culture media limit embryonic development. Culturing IVP bovine embryos in standard IVP bovine embryo culture media conditioned with oviduct and/or endometrial cells improves blastocyst formation and reduces the time to formation. Abstract: In vitro embryo production in cattle greatly impacts blastomere biochemistry, embryo rate of development and pre- and post-transfer survival. In vivo, the bovine embryo migrates through the oviduct isthmus before entering the uterus on approximately day 4 of development where it remains unattached within the uterine lumen until day 20 of gestation. During this time, the embryo is sequentially exposed to oviduct followed by endometrial secretions that support embryonic development. Considering this, we tested the effect of culturing in vitro produced (IVP) bovine embryos sequentially in oviduct epithelial- (OEp; days 1-3) followed by endometrial epithelial- (EEp) or EEp and fibroblast cell (EEp/F; days 4-8)-conditioned media on embryonic development using a time-lapse monitoring system. Compared to control, culturing IVP embryos in EEp- or EEp/F-conditioned media without prior culture in OEp-conditioned media increased blastocyst formation (P < 0.05) and reduced the time to blastocyst formation (P < 0.05). Culturing IVP bovine embryos in OEp-conditioned media followed by EEp- or EEp/F-conditioned media, however, had the greatest impact on embryo developmental kinetics and increased morula and blastocyst formation (P < 0.05) and reduced time to formation (P < 0.05). Day 8 blastocyst cell numbers, diameter and quality were not significantly different, although, blastocyst quality scores were less (indicative of better quality) for all cell-conditioned media compared to control. In conclusion, IVP bovine embryo development may be improved using a sequential embryo culture system involving bovine oviduct followed by endometrial cell-conditioned media.

Identification of fallopian tube microbiota and its association with ovarian cancer.

Investigating the human fallopian tube (FT) microbiota has significant implications for understanding the pathogenesis of ovarian cancer (OC). In this large prospective study, we collected swabs intraoperatively from the FT and other surgical sites as controls to profile the microbiota in the FT and to assess its relationship with OC. Eighty-one OC and 106 non-cancer patients were enrolled and 1001 swabs were processed for 16S rRNA gene PCR and sequencing. We identified 84 bacterial species that may represent the FT microbiota and found a clear shift in the microbiota of the OC patients when compared to the non-cancer patients. Of the top 20 species that were most prevalent in the FT of OC patients, 60% were bacteria that predominantly reside in the gastrointestinal tract, while 30% normally reside in the mouth. Serous carcinoma had higher prevalence of almost all 84 FT bacterial species compared to the other OC subtypes. The clear shift in the FT microbiota in OC patients establishes the scientific foundation for future investigation into the role of these bacteria in the pathogenesis of OC.

Sex matters in preclinical research.

International Women's Day 2024 has a theme of inclusion. As publishers of preclinical research, we aim to show how inclusion of females in research advances scientific rigor and improves treatment reliability. Sexual reproduction is key to all life across the plant and animal kingdoms. Biological sex takes many forms that are morphologically differentiated during development: stamens versus pistils in plants; color and plumage in birds; fallopian tubes versus vas deferens in mammals; and differences in size, for instance, males are smaller in the fruit fly Drosophila melanogaster. Physical differences may be obvious, but many traits may be more obscure, including hormonal, physiological and metabolic factors. These traits have a big influence on disease and responses to treatment. Thus, we call for improved inclusion, analysis and reporting of sex as a biological variable in preclinical animal modeling research.

Ovarian Cancer in the Older Manitoban Population-Treatment Tolerance and Cancer-Related Outcomes: A Manitoba Ovarian Cancer Outcomes (MOCO) Group Study.

BACKGROUND: In Canada, individuals with gynecologic reproductive organs (ovaries, fallopian tubes, uterus) over the age of 70 comprise a large proportion of epithelial ovarian cancer patients. These patients often have co-morbidities, polypharmacy, or decreased functional status that may impact treatment initiation and tolerance. Despite this, there is limited evidence to guide treatment for older patients diagnosed with ovarian epithelial carcinoma. METHODS: This is a retrospective study with data from Manitoba, Canada. The data were obtained from the Manitoba Ovarian Cancer Database, the Manitoba Cancer Registry, and electronic health records. All individuals with epithelial ovarian, fallopian tube, or peritoneal cancer diagnosed between 2009 and 2018 were identified. Patients aged > 70 at the time of diagnosis were included in the study cohort. RESULTS: Four hundred and forty individuals were included. The majority had advanced stage disease (56%). Moreover, 59% of patients received no chemotherapy. Of the patients who received chemotherapy, 20% received <2 cycles and 21% required a dose reduction due to toxicity. Univariable and multivariable analysis identified advanced stage (p < 0.001), treatment modality (p < 0.001), and advanced age at diagnosis (p < 0.001) with poorer overall survival. CONCLUSIONS: Our study demonstrated a high rate of chemotherapy dose reduction and discontinuation in the elderly epithelial ovarian cancer population. Further research is needed to identify risk factors for treatment discontinuation and intolerance in this population.

Successful management of an advanced interstitial ectopic pregnancy in a resource-limited setting: a case report.

BACKGROUND: Interstitial ectopic pregnancy is an ectopic gestation developing in the uterine part of the fallopian tube. The condition is rare and presents challenges for clinical as well as radiological diagnosis. This case report presents a rare case of interstitial ectopic pregnancy diagnosed intraoperatively. CASE PRESENTATION: A 36-year-old Black woman, referred from a peripheral health facility, presented at the emergency department with severe abdominal pains, vaginal spotting, nausea, and vomiting, with a 2-month history of irregular menstrual flow. Clinical and laboratory findings were suggestive of an acute abdomen likely due to a ruptured ectopic pregnancy (ultrasound was not available). An emergency exploratory laparotomy was done, which revealed a right adnexal ruptured interstitial pregnancy of a lifeless female fetus weighing 500 g (estimated mean gestational age of 22-23 weeks). The left fallopian tube looked normal. The site of rupture was repaired, followed by cleaning and closure of the abdomen. The post-operative period was uneventful, and the patient was discharged on postoperative day 7. CONCLUSION: Interstitial pregnancies are uncommon and rarely attain advanced gestational ages, as in this case, compared with other tubal ectopic pregnancies. However, women presenting with signs of hypovolemic shock and acute abdomen, with a positive pregnancy test, warrant a high index of suspicion.

The role of the oviduct environment in embryo survival.

CONTEXT: Declining fertility is an issue in multiple mammalian species. As the site of fertilisation and early embryo development, the oviduct plays a critical role in embryo survival, yet there is a paucity of information on how the oviduct regulates this process. AIMS: We hypothesised that differences in steroid hormone signalling and/or immune function would be observed in a model of poor embryo survival, the peripubertal ewe. METHODS: We examined expression of steroid hormones in systemic circulation, oviductal expression of oestrogen receptorαand genes important in steroid hormone signalling, and immune function in pregnant and cyclic peripubertal and adult ewes on day 3 after oestrus. KEY RESULTS: Concentrations of progesterone, but not oestradiol, were decreased in the peripubertal ewe compared to the adult ewe. Oestrogen receptorαprotein expression was increased in the peripubertal ewe, but pathway analysis of gene expression revealed downregulation of the oestrogen signalling pathway compared to the adult ewe. Differential expression of several genes involved in immune function between the peripubertal and adult ewe was consistent with an unfavourable oviductal environment in the peripubertal ewe lamb. Oestradiol concentration was positively correlated with the expression of multiple genes involved in the regulation of immune function. CONCLUSIONS: Differences in the immune environment of the oviduct, potentially linked to differential modulation by steroid hormones, may partially underly the poor fertilisation and early embryo survival observed in the peripubertal ewe. IMPLICATIONS: A unfavourable oviductal environment may play an important role in limiting reproductive success.

Locus-specific LINE-1 expression in clinical ovarian cancer specimens at the single-cell level.

Long interspersed nuclear elements (LINE-1s/L1s) are a group of retrotransposons that can copy themselves within a genome. In humans, it is the most successful transposon in nucleotide content. L1 expression is generally mild in normal human tissues, but the activity has been shown to increase significantly in many cancers. Few studies have examined L1 expression at single-cell resolution, thus it is undetermined whether L1 reactivation occurs solely in malignant cells within tumors. One of the cancer types with frequent L1 activity is high-grade serous ovarian carcinoma (HGSOC). Here, we identified locus-specific L1 expression with 3' single-cell RNA sequencing in pre- and post-chemotherapy HGSOC sample pairs from 11 patients, and in fallopian tube samples from five healthy women. Although L1 expression quantification with the chosen technique was challenging due to the repetitive nature of the element, we found evidence of L1 expression primarily in cancer cells, but also in other cell types, e.g. cancer-associated fibroblasts. The expression levels were similar in samples taken before and after neoadjuvant chemotherapy, indicating that L1 transcriptional activity was unaffected by clinical platinum-taxane treatment. Furthermore, L1 activity was negatively associated with the expression of MYC target genes, a finding that supports earlier literature of MYC being an L1 suppressor.

Immunohistochemical and molecular pattern of p53 in epithelial ovarian cancers negative for germline BRCA1/2 variants.

Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and "p53 signature" is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and "p53 signature" in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.

Unusual presentation of late-stage ectopic tubal pregnancy (19 weeks' gestation): Case report and literature review.

Ectopic pregnancy is a medical condition in which a fertilized egg takes an unexpected detour away from the uterine cavity and the fallopian tube becomes a popular host, with the ampulla being the prime location. However, it can occur in other areas such as cervix, ovaries, or abdomen. The most common risk factors are pelvic inflammatory disease, previous pelvic or abdominal surgery, abnormal anatomy of genital organs, endometriosis, previous ectopic pregnancies, assisted reproductive technologies, endocrine disorders, and even the subtle influence of low-dose progestins from contraceptives. We will present a rare case of unrecognized late-stage tubal ectopic pregnancy. The following case report is of a 25-year-old Caucasian female patient (G2, P0) who presented to the emergency department with a 24-hour abdominal pain syndrome. The patient did not have a gynecological examination for this reason. During the examination, taking into account the clinical and ultrasound findings, a suspicion of pregnancy in a bicornuate uterus was raised, and an MRI of the pelvis was performed. MRI showed ectopic pregnancy in the left fallopian tube with a properly developed fetus that corresponded to a gestation of 19 weeks. An emergency laparotomy was performed and the left fallopian tube with the fetus was removed. The early and late course of recovery went smoothly. The patient was discharged after adequate clinical development.

Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells.

High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a ß-adrenergic receptor-dependent (ß-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the ß-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.