Preeclampsia is a unique multiple system disorder that affects 5% to 8% of pregnancies. Exosomes, membrane-encapsulated vesicles that are released into the extracellular environment by many cell types, can carry signals to the recipient cells to affect inflammation, apoptosis, and angiogenesis. We hypothesize that exosomes from women with preeclampsia complications impair vascular development by delivering antiangiogenic factors to endothelial cells. In the current study, plasma samples from gestational age-matched preeclampsia and normal pregnancies were used to isolate circulating exosomes by commercial kits. Next, application of transwell and matrigel tube formation assays showed that exosomes from preeclampsia patients impaired angiogenesis of human umbilical vein endothelial cells. We found that exosomes from preeclampsia expressed abundant sFlt-1 (soluble fms-like tyrosine kinase-1) and sEng (soluble endoglin). Considering the possibility that extracellular sFlt and sEng were horizontally transferred to human umbilical vein endothelial cells, we successfully collected exosomes containing high levels of sFlt-1 and sEng by overexpressing them in human embryonic kidney 293 cells. Furthermore, we demonstrated that these exosomes can attenuate the proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. In a mouse model, exosomes from preeclampsia patients caused vascular dysfunction directly resulted in adverse preeclampsia-like birth outcomes. Thus, we proposed that exosomes mediated efficient transfer of sFlt-1 and sEng to endothelial cells to damage vascular functions and induce complications in preeclampsia patients.

Aims: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ⁹-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. Methods: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. Results: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Conclusion: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68 þ CD163 þ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERa), but not ERb. Mechanistic investigations revealed that CD68 þ CD163 þ macrophages secreted cytokines, such as IL17A, that upregulated ERa expression through TET1-mediated epigenetic modulation of the ERa gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERa expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting.

Background/Aims: In this study, a subpopulation of stem-like cells in human high grade serous ovarian carcinomas (ovarian cancer stem cells; OCSCs) were isolated and characterized. Methods: Primary high-grade serous ovarian carcinoma (HGSC) fresh biopsies were cultured under serum-free conditions to produce floating spheres. Sphere formation assay, including self-renewal, differentiation potential, chemo-resistance, and tumorigenicity were determined in vitro or in vivo. Results: OCSCs overexpressed stem cell genes (Oct-4, Nanog, Sox-2, Bmi-1, Nestin, CD133, CD44, CD24, ALDH1, CD117, and ABCG2). Immunostaining of spheres showed overexpressed Oct-4, Nanog, and Sox-2. These isolated tumor cells expanded as spheroid colonies for more than 30 passages. In contrast, adherent cells expressed high levels of CA125 and CK7. Flow cytometry analysis showed increased CSC markers (CD44, CD24, CD117, CD133, ABCG2, and ALDH1) in the spheroid cell population. OCSCs displayed higher chemoresistance to cisplatin or paclitaxel compared to adherent cells. Moreover, subcutaneous injection of 1 × 104 sphere-forming cells into NOD/SCID mice gave rise to new tumors similar to the original human tumors and could be passaged in mice. Conclusion: These results revealed that HGSCs are created and propagated by a small number of undifferentiated tumorigenic cells, and therapeutic targeting of these cells could be beneficial for treatment of HGSCs.

Exosomes have recently emerged as key mediators of different physiological and pathological processes. However, there has been few report about proteomic analysis of exosomes derived from human follicular fluid and their association with the occurrence of PCOS. Herein, we used TMT‐tagged quantitative proteomic approach to identify proteomic profiles in exosomes derived from follicular fluid of PCOS patients and healthy controls. We identified 662 proteins in exosomes derived from human ovarian follicular fluid. Eighty‐six differently expressed proteins (P < .05) were found between PCOS and healthy women. The alterations in the proteomic profile were related to the inflammation process, reactive oxygen species metabolic process, cell migration and proliferation. Importantly, we observed that follicular fluid exosomes contain S100 calcium‐binding protein A9 (S100‐A9) protein. Exosome‐enriched S100‐A9 significantly enhanced inflammation and disrupted steroidogenesis via activation of nuclear factor kappa B (NF‐κB) signalling pathway. These data demonstrate that exosomal proteins are differentially expressed in follicular fluid during disease process, and some proteins may play important roles in the regulation of granulosa cell function. These results highlight the importance of exosomes as extracellular communicators in ovarian follicular development.