The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer.

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.

Maternal plasma angiogenic index-1 (placental growth factor/soluble vascular endothelial growth factor receptor-1) is a biomarker for the burden of placental lesions consistent with uteroplacental underperfusion: a longitudinal case-cohort study.

BACKGROUND: Placental lesions consistent with maternal vascular underperfusion (MVU) are thought to be pathogenically linked to preeclampsia, small-for-gestational-age newborns, fetal death, and spontaneous preterm labor and delivery; yet, these lesions cannot be diagnosed antenatally. We previously reported that patients with such conditions and lesions have an abnormal profile of the angiogenic placental growth factor (PlGF) and antiangiogenic factors (eg, soluble vascular endothelial growth factor receptor [sVEGFR]-1). OBJECTIVE: The objectives of this study were to: (1) examine the relationship between the maternal plasma PlGF/sVEGFR-1 concentration ratio (referred to herein as angiogenic index-1) and the burden of histologic placental features consistent with MVU; and (2) test the hypothesis that angiogenic index-1 can identify patients in the midtrimester who are destined to deliver before 34 weeks of gestation with multiple (ie, ≥3) histologic placental features consistent with MVU. STUDY DESIGN: A 2-stage case-cohort sampling strategy was used to select participants from among 4006 women with singleton gestations enrolled from 2006 through 2010 in a longitudinal study. Maternal plasma angiogenic index-1 ratios were determined using enzyme-linked immunosorbent assays. Placentas underwent histologic examination according to standardized protocols by experienced pediatric pathologists who were blinded to clinical diagnoses and pregnancy outcomes. The diagnosis of lesions consistent with MVU was made using criteria proposed by the Perinatal Section of the Society for Pediatric Pathology. Weighted analyses were performed to reflect the parent cohort; "n*" is used to reflect weighted frequencies. RESULTS: (1) Angiogenic index-1 (PlGF/sVEGFR-1) concentration ratios were determined in 7560 plasma samples collected from 1499 study participants; (2) the prevalence of lesions consistent with MVU was 21% (n* = 833.9/3904) and 27% (n* = 11.4/42.7) of women with ≥3 MVU lesions delivered before 34 weeks of gestation; (3) a low angiogenic index-1 (<2.5th quantile for gestational age) in maternal plasma samples obtained within 48 hours of delivery had a sensitivity of 73% (n* = 8.3/11.4; 95% confidence interval [CI], 47-98%), a specificity of 94% (n* = 3130.9/3316.2; 95% CI, 94-95%), a positive likelihood ratio of 12.2, and a negative likelihood ratio of 0.29 in the identification of patients who delivered placentas with ≥3 MVU lesions at <34 weeks; (4) prospectively, at 20-23 weeks of gestation, a maternal plasma concentration of angiogenic index-1 <2.5th quantile identified 70% (n* = 7.2/10.3; 95% CI, 42-98%) of patients who delivered placentas with ≥3 MVU lesions before 34 weeks (specificity, 97% [n* = 2831.3/2918; 95% CI, 96-98%]; positive likelihood ratio, 23; negative likelihood ratio, 0.31); and (5) among women without obstetrical complications who delivered at term, angiogenic index-1 was lower in women with than without placental lesions consistent with MVU (P < .05). CONCLUSION: Maternal plasma angiogenic index-1 (PlGF/sVEGFR-1) is the first biomarker for the burden of placental lesions consistent with MVU. We propose that an accumulation of these lesions in placentas delivered before 34 weeks is a histologic counterpart of an antiangiogenic profile.

Increasing of syncytial knot and fibrinoid deposit in high-Cd accumulated human placentas / Aumento del nodo sincicial y depósitos de fibrinoide en placenta humanas con alta acumulación de cadmio

A toxic metal, cadmium (Cd), can accumulate in human organs. Placenta is usually used as indicator organ for Cd exposure. Therefore, we aim to investigate the different of placental morphology between the low- and high-Cd accumulated placentas. The samples were collected from 14 pregnant women who resided in low-Cd contaminated (L-Cd group) and high-Cd contaminated (H-Cd group) areas. The concentrations of Cd in blood (B-Cd), urine (U-Cd) and placentas (P-Cd) were measured by ICP-MS and AAS. The morphological appearance of placentas was examined by using routine paraffin section and H & E staining. The results showed that levels of B-Cd, U-Cd and P-Cd were significantly higher in H-Cd group than in L-Cd group (p= 0.001). Moreover, the B-Cd was positively correlated with U-Cd (rs= 0.823, p= 0.000) and P-Cd concentrations (rs= 0.854, p= 0.000). The appearances of syncytial knot (STK) and fibrinoid deposit (Fd) were obviously greater in H-Cd group than in L-Cd group (p= 0.007, p= 0.026). The STK was positively correlated with both Fd (rs= 0.572, p= 0.032) and P-Cd concentration (rs= 0.766, p= 0.001). Although the chorioamnitis and decidual inflammation features were found in both groups but the appearance in H-Cd group seems to be more severe than in L-Cd group. From these results, we suggested that high Cd level in placenta may be involved in morphological changes, especially STK and Fd increasing and probably disturb the connection between maternal and fetal circulation.

Un metal tóxico, el cadmio (Cd), se puede acumular en órganos humanos. La placenta se utiliza, por lo general, como órgano indicador de la exposición a Cd. Nuestro objetivo fue investigar la diferente morfología placentaria entre las placentas con baja y alta acumulación de Cd. Las muestras fueron recolectadas de 14 mujeres embarazadas que residían áreas con alta (grupo H-Cd) y baja contaminación por Cd (grupo L-Cd). Las concentraciones de Cd en la sangre (B- Cd), orina (U-Cd) y placentas (P-Cd) se midieron por ICP-MS y AAS. La apariencia morfológica de las placentas fue examinada usando cortes histológicos teñidos con H-E. Los resultados mostraron que los niveles de B-Cd, U-Cd y P-Cd fueron significativamente mayores en el grupo H-Cd (p= 0,001). Por otra parte, el B-Cd se correlacionó positivamente con las concentraciones de U-Cd (rs= 0,854, p = 0,000 ) y P-Cd (rs= 0,823, p = 0,000). Las apariciones de nodos sinciciales (NS) y depósitos fibrinoides (Fd) fueron mayores en el grupo H-Cd (rs= 0,007, p= 0,026). Los ND se correlacionaron positivamente con los Fd (rs= 0,572, p= 0,032) y la concentración de P-Cd (rs= 0,766, p = 0,001). Aunque características de corioamnitis e inflamación de la decidua se encontraron en ambos grupos, su aparición en el grupo H-Cd pareció ser más grave que en el grupo L-Cd. A partir de estos resultados, sugerimos que el nivel alto de Cd en la placenta puede estar involucrado en los cambios morfológicos, especialmente el aumento de NS y Fd, los que probablemente alteran la relación entre la circulación materna y fetal.

Analysis of syncytial nuclear aggregates in preeclampsia shows increased sectioning artefacts and decreased inter-villous bridges compared to healthy placentas.

Syncytial nuclear aggregates (SNAs) are increased in pregnancy complications and include 'true' syncytial knots and inter-villous bridges. Apparent nuclear overlay caused by sectioning artefacts are frequently counted from single sections. Haematoxylin and eosin stained serial sections were assessed for frequency of SNA subtypes in placentas from normal, preeclamptic and fetal growth restricted (FGR) pregnancies. There were more sectioning artefacts and syncytial knots and fewer bridges in samples from preeclampsia compared to controls. There were no significant differences between FGR and control samples. This suggests the villous tree in preeclampsia has less inherent structural support and trophoblast cell dynamics are different.

Histomorphometry of preterm and term human placentas / Histomorfometría de placentas de pretérmino y término

The intra-uterine existence of foetus is dependent on placenta, a major organ of nutrition and homeostasis.The present study was carried out to compare morphometric and histological changes in preterm and term human placentas. Eighty placentas collected from Department of Obstetrics and Gynecology, JNMCH, AMU, Aligarh, were divided into group first of preterm placentas up to 36 weeks (n =30) and second group of full term placentas i.e. 37 to 40 weeks ( n = 50) respectively. The samples were fixed in 10 percent formol-saline solution. The gross morphological variables of placentas were studied. There was a significant increase in the placental weight, decidual area and umbilical cord diameter of term placenta as compared to that of the preterm ones. From each placenta whole thickness tissue blocks were taken and processed for paraffin sectioning. Five µ-thick sections were stained with Haematoxylin-eosin and Van Gieson stains and processed for light microscopy. A total of 200 villi were studied in each sample under high power field and occurrence of different features was expressed as percentages for each parameter. The appearance of microvilli and syncytial bud on the syncytium were almost absent in the villi of term placentas. It was concluded that with increasing gestational age there was a gradual increase in the number of capillaries in villi from preterm to term placenta.There was a significant increase in syncytial knot count, fibrinoid necrosis, vasculosyncytial membrane and decrease in the percentage of villi showing cytotrophoblastic cells and number of Hofbauer cells in term group as compared to preterm group.

La existencia intrauterina del feto depende de la placenta, el mayor órgano de nutrición y homeostasis. El estudio se llevó a cabo para comparar los cambios morfométricos e histológicos de la placenta humana de término y pretérmino. Ochenta placentas fueron obtenidas del Departamento de Obstetricia y Ginecología, JNMCH, AMU, Aligarh y se dividieron en grupos, el primer grupo de placentas de pretérmino hasta 36 semanas (n = 30) y el segundo grupo de placentas de término, de 37 a 40 semanas (n = 50 ). Las muestras fueron fijadas en solución de formol-salina al 10 por ciento. Se estudiaron las variables morfológicas macroscópicas de las placentas. Hubo un aumento significativo en el peso de la placenta, el área de decidua y el diámetro del cordón umbilical de la placenta a término en comparación con la de los prematuros. De cada placenta se tomaron y se procesaron bloques de tejido para incluirlos en parafina. Cortes de 5 µm fueron teñidos con HE y Van Gieson para microscopía óptica. De cada muestra fueron estudiadas 200 vellosidades, bajo campo de alta resolución y la aparición de diferentes características se expresó como porcentajes para cada parámetro. La aparición de las microvellosidades y brote sincitial en el sincitio estaban casi ausente en las vellosidades de las placentas de término. Se puede concluir que al aumentar la edad gestacional hubo un aumento gradual en el número de capilares en las vellosidades de la placenta de término. Existe un aumento significativo en el recuento de nudo sincitial, necrosis fibrinoide, membrana vasculosincisial y disminución en el porcentaje de las vellosidades que muestran células citotrofoblástica y número de células de Hofbauer en las placentas del término de grupo en comparación con el grupo de pretérmino.

Vasculosyncytial membrane in relation to syncytial knots complicates the placenta in preeclampsia: a histomorphometrical study.

The vasculosyncytial membrane (VSM), primary site of fetomaternal exchange is formed when syncytiotrophoblast surrounds the terminal villi and make a close contact with capillaries. Some syncytiotrophoblast forms thin single layer of villous and some syncytial nuclei become piled up to form the syncytial knots (SKs). Undoubtedly there is a clear-cut inverse relation between villous VSM and fetal hypoxia. In preeclampsia (PE) the hypoxia injury disrupts the syncytial architecture which in turn initiates other complications of PE. Present study was designed to observe the morphological and histomorphometric features of 84 placentas from control and PE (42 each) collected from Department of Obstetrics and Gynecology. Neonatal weight and placental weight were reduced in PE than the controls but the feto-placental index did not differ. The SK density and VSM thickness was found to be increased and was statistically significant in PE cases. In relation to SKs, the VSM thickness was twofold increased than the controls and was statistically significant. The SKs in the present study were classified as type-1, 2a, 2b, and 3. Type 1 was found to be 62% in control and 47% in PE, type 2a and 2b were 38% in control and 37% in PE, and type 3 was in 8% of PE cases. All the parameters of present study reveal the adverse effects of PE influencing on both morphological and microscopical features of the placenta resulting in fetal hypoxia.

Vasculosyncytial membrane in relation to syncytial knots complicates the placenta in preeclampsia: a histomorphometrical study / 대한해부학회지

The vasculosyncytial membrane (VSM), primary site of fetomaternal exchange is formed when syncytiotrophoblast surrounds the terminal villi and make a close contact with capillaries. Some syncytiotrophoblast forms thin single layer of villous and some syncytial nuclei become piled up to form the syncytial knots (SKs). Undoubtedly there is a clear-cut inverse relation between villous VSM and fetal hypoxia. In preeclampsia (PE) the hypoxia injury disrupts the syncytial architecture which in turn initiates other complications of PE. Present study was designed to observe the morphological and histomorphometric features of 84 placentas from control and PE (42 each) collected from Department of Obstetrics and Gynecology. Neonatal weight and placental weight were reduced in PE than the controls but the feto-placental index did not differ. The SK density and VSM thickness was found to be increased and was statistically significant in PE cases. In relation to SKs, the VSM thickness was twofold increased than the controls and was statistically significant. The SKs in the present study were classified as type-1, 2a, 2b, and 3. Type 1 was found to be 62% in control and 47% in PE, type 2a and 2b were 38% in control and 37% in PE, and type 3 was in 8% of PE cases. All the parameters of present study reveal the adverse effects of PE influencing on both morphological and microscopical features of the placenta resulting in fetal hypoxia.

Vasculosyncytial membrane in relation to syncytial knots complicates the placenta in preeclampsia: a histomorphometrical study / 대한해부학회지

The vasculosyncytial membrane (VSM), primary site of fetomaternal exchange is formed when syncytiotrophoblast surrounds the terminal villi and make a close contact with capillaries. Some syncytiotrophoblast forms thin single layer of villous and some syncytial nuclei become piled up to form the syncytial knots (SKs). Undoubtedly there is a clear-cut inverse relation between villous VSM and fetal hypoxia. In preeclampsia (PE) the hypoxia injury disrupts the syncytial architecture which in turn initiates other complications of PE. Present study was designed to observe the morphological and histomorphometric features of 84 placentas from control and PE (42 each) collected from Department of Obstetrics and Gynecology. Neonatal weight and placental weight were reduced in PE than the controls but the feto-placental index did not differ. The SK density and VSM thickness was found to be increased and was statistically significant in PE cases. In relation to SKs, the VSM thickness was twofold increased than the controls and was statistically significant. The SKs in the present study were classified as type-1, 2a, 2b, and 3. Type 1 was found to be 62% in control and 47% in PE, type 2a and 2b were 38% in control and 37% in PE, and type 3 was in 8% of PE cases. All the parameters of present study reveal the adverse effects of PE influencing on both morphological and microscopical features of the placenta resulting in fetal hypoxia.