RESUMO
Zona pellucida 3 (ZP3) expression is classically found in the ZP-layer of the oocytes, lately shown in ovarian and prostate cancer. A successful ZP3 ovarian cancer immunotherapy in transgenic mice suggested its use as an attractive therapeutic target. The biological role of ZP3 in cancer growth and progression is still unknown. We found that ~88% of the analyzed adenocarcinoma, squamous and small cell lung carcinomas to express ZP3. Knockout of ZP3 in a ZP3-expressing lung adenocarcinoma cell line, significantly decreased cell viability, proliferation, and migration rates in vitro. Zona pellucida 3 knock out (ZP3-KO) cell tumors inoculated in vivo in immunodeficient non-obese diabetic, severe combined immunodeficient mice showed significant inhibition of tumor growth and mitigation of the malignant phenotype. RNA sequencing revealed the deregulation of cell migration/adhesion signaling pathways in ZP3-KO cells. This novel functional relevance of ZP3 in lung cancer emphasized the suitability of ZP3 as a target in cancer immunotherapy and as a potential cancer biomarker.
RESUMO
Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed. Data on the membrane progesterone receptors (mPRs) regulated signaling pathways in ULs in the available literature is still very limited. One of the essential characteristics of ULs is the excessive production of extracellular matrix (ECM). P4 has been shown to stimulate ECM production and collagen synthesis in ULs. Recent research demonstrated that, despite their benign nature, ULs may present with abnormal vasculature. P4 has been shown to regulate angiogenesis in ULs through the upregulation of vascular endothelial growth factor (VEGF) and by controlling the secretion of permeability factors. This review summarizes the key findings regarding the role of PGRs and mPRs in ULs, especially highlighting the potential ECM and angiogenesis modulation by P4. An increased understanding of this mechanistic role of nuclear and specifically mPRs in the biology of P4-modulated ECM and angiogenesis in the growth of ULs could turn out to be fundamental for developing effective targeted therapies for ULs.
Assuntos
Leiomioma , Progesterona , Receptores de Progesterona , Transdução de Sinais , Neoplasias Uterinas , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Progesterona/metabolismo , Feminino , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Neoplasias Uterinas/tratamento farmacológico , Receptores de Progesterona/metabolismo , Matriz Extracelular/metabolismo , Terapia de Alvo MolecularRESUMO
OBJECTIVE: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth, synthesis, and accumulation of the extracellular matrix in uterine leiomyomas. DESIGN: Laboratory study. SETTING: Academic Research Institutions. PATIENTS (S): This study involved reproductive-age women diagnosed with infertility associated uterine leiomyomas who underwent myomectomy either after selective progesterone receptor modulator ulipristal acetate (UA) treatment or without any pharmacological pretreatment. Control samples included healthy myometrium tissue (n = 100). Specimens were obtained from the Department of Reproduction and Gynecological Endocrinology and Biobank, Medical University of Bialystok, Poland. INTERVENTIONS: Daily (5 mg/d) UA treated for 2 months (n = 100) and untreated (n = 150) patients with uterine leiomyomas or normal healthy myometrium (n = 100) tissue samples immediately after surgery were collected for transcriptional analysis and assessments. MAIN OUTCOME MEASURES: Progesterone-induced activation of the signaling pathways related to uterine leiomyomas extracellular matrix synthesis, deposition, and growth, as well as the expression profile of progesterone receptors in uterine leiomyomas, were assessed. RESULTS: The results indicated that progesterone activated the transforming growth factor-ß and SMAD3 signaling pathways and promoted proliferation, growth, and extracellular matrix remodeling in uterine leiomyomas by up-regulating SMAD3, transforming growth factor-ß (TGF-ß) receptor type 1 and II, Ras homolog A, vascular endothelial growth factor, or increasing the fibrosis-related gene collagen, type I, É-1, and procollagen, type I, É-1 production. In contrast, UA had inhibitory effects on these processes. The study also showed that both nuclear and membrane progesterone receptors play distinct roles in uterine leiomyoma pathobiology. CONCLUSIONS: We showed that both nuclear and membrane progesterone receptors were relevant in the treatment of uterine leiomyomas, especially when combined with selective progesterone receptor modulators. Novel therapeutic approaches combining selective progesterone receptor modulators with or without direct and indirect extracellular matrix targeting through selected specifically TGF-ß and SMAD3 (SMAD3, TGF-ß receptor types 1 and II, Ras homolog A, vascular endothelial growth factor, collagen, type I, É-1) signaling pathways could therefore be a treatment option for uterine leiomyomas.
Assuntos
Leiomioma , Norpregnadienos , Progesterona , Receptores de Progesterona , Transdução de Sinais , Neoplasias Uterinas , Humanos , Feminino , Leiomioma/tratamento farmacológico , Leiomioma/metabolismo , Leiomioma/patologia , Leiomioma/cirurgia , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia , Neoplasias Uterinas/genética , Receptores de Progesterona/metabolismo , Norpregnadienos/farmacologia , Norpregnadienos/uso terapêutico , Progesterona/farmacologia , Progesterona/metabolismo , Adulto , Transdução de Sinais/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Proteína Smad3/metabolismo , Miomectomia Uterina , Estudos de Casos e Controles , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Miométrio/patologiaRESUMO
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.
Assuntos
Humanos , Feminino , Microvilosidades , Placenta/anatomia & histologiaRESUMO
Both the feet of six human foetuses of different age groups having unilateral club feet, were dissected for morphological study. Six morphometric parameters considered for comparing gross anatomical changes in normal and deformed feet, were 1-Maximum length of the talus, 2-Longitudinal dimension of head of talus, 3-Anterior trochlear breadth, 4-Maximum medial talar height, 5-Talar neck and calcaneal angle, 6-Talocalcaneal angle. All the foetuses with congenital club feet have almost similar deformity of foot skeleton. The gross anomalies observed were the smaller size of club foot talus and increased medial and planter deviation of a stunted, misshapen head and neck region. A medial plantar subluxation of the navicular bone with a consequent deformity of the articular facets of the talar head was also observed. Uniformity and consistency of anatomical abnormalities were striking features in present study.
Para su estudio morfológico fueron disecados ambos pies de seis fetos humanos de distintas edades, uno de los pies era zambo. Seis parámetros morfométricos fueron considerados para la comparación de graves alteraciones anatómicas en los pies normales y deformes; estos fueron: 1. Longitud máxima del talus, 2. Dimensión longitudinal de la cabeza del talus, 3. Ancho troclear anterior, 4. Altura medial máxima del talus, 5. Cuello talar y ángulo calcáneo, 6. Ángulo talocalcáneo. Todos los fetos con pie zambo congénito tienen una deformidad similar del esqueleto del pie. Las anomalías graves observadas fueron el menor tamaño del talus del pie zambo, aumento de la desviación media y retraso en el crecimiento plantar, deformación de la cabeza y región del cuello talar. También se observó una subluxación medial plantar del hueso navicular, con un consecuente deformidad de las facetas articulares de la cabeza del talus. La uniformidad y consistencia de las anomalías anatómicas fueron los rasgos más llamativos en este estudio.
Assuntos
Feminino , Feto/anatomia & histologia , Feto/anormalidades , Pé Torto/diagnóstico , Pé Torto/embriologia , Pé Torto/patologia , Calcâneo/anormalidades , Morfogênese , TálusRESUMO
Lumbosacral part of the spinal canal requires special attention because this is the site commonly involved in spina bifida, tethered cord syndrome and some other pathologies like fatty tumours in the spine, cysts and syrinxes. The diagnosis as well as the treatment of neural tube defects mandates an accurate knowledge of morphometry of lumbosacral vertebral canal. There are various reports on radiological morphometric measurements in human foetuses by various authors but these possess inherent variability due to imaging techniques, patient positioning, observer's measuring techniques and normal and pathological variations. To overcome all these limitations, direct measurements by vernier calliper were preferred. 30 Formalin preserved human foetuses, of all age groups and both sexes, free of congenital craniovertebral anomalies, were obtained from the museum of Dept. of Anatomy, J. N. Medical College AMU Aligarh for the present study. Foetuses were divided into five groups (I-V) based on their gestational ages. Group I foetuses were of less than 17 weeks, II of 17-20 weeks, III of 21-25 weeks, IV of 26-30 weeks and V of more than 30 weeks. Each group contained 6 foetuses having both male and female, 3 each. Morphometric parameters taken into account were length of lumbar canal, maximum transverse diameters of lumbar vertebral canal at different vertebral levels, heights of the posterior surfaces of bodies of all lumbar vertebrae and length of sacral canal. Readings of adjacent groups were compared and results were analyzed by using Student's 't' test. Lumbar canal starts growing in length significantly in group III foetuses onward. There was consistency in the growth of lumbar canal diameters with gestational age at all levels. Heights of vertebral bodies of Ist two lumbar vertebrae showed variability in some adjacent groups. The same in the next three grew constantly with the growth of foetuses. Sacral canal showed variable growth in lengths in different grou...
La porción lumbosacra del canal espinal requiere una atención especial; es un sitio frecuentemente implicado en la espina bífida, el síndrome de médula anclada y algunas otras patologías como tumores de grasa en la columna vertebral, quistes y siringomelia. El diagnóstico y el tratamiento de los defectos del tubo neural requieren de un conocimiento preciso de la morfometría del canal vertebral lumbosacro. Existen diversos informes radiológicos sobre mediciones morfométricas en fetos humanos por parte de diversos investigadores, pero estos poseen una variabilidad inherente debido a las técnicas de imagen, posicionamiento del paciente, técnicas de medición del observador y, las variaciones normales y patológicas. Para superar todas estas limitaciones, para las mediciones directas se utilizó un caliper vernier. 30 fetos humanos conservados en formalina, de todas las edades y de ambos sexos, sin anomalías congénitas craneovertebrales, fueron obtenidos del museo del Departamento de Anatomía, J. N. Facultad de Medicina de la UMA, Aligarh. Los fetos fueron divididos en cinco grupos (I-V) sobre la base de su edad gestacional. El grupo I de fetos fueron los menores de 17 semanas, el II de 17-20 semanas, el III de 21-25 semanas, IV de 26 a 30 semanas, V de más de 30 semanas. Cada grupo contenía 6 fetos de ambos sexos (1:1/H:M)). Los parámetros morfométricos tomados en cuenta fueron la longitud del canal lumbar, el diámetro transversal máximo del canal vertebral lumbar en diferentes niveles, la altura de las superficies posteriores de los cuerpos de todas las vértebras lumbares y la longitud del canal sacro. Las mediciones de los grupos fueron comparadas y analizadas mediante el uso de la prueba de "t". El canal lumbar comenzó a aumentar en longitud significativamente desde el grupo de fetos III en adelante. No hubo consistencia en el crecimiento de los diámetros del canal lumbar con la edad gestacional en todos los niveles. Las alturas de los primeros dos cuerpos verte...