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High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.
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Neoplasias Ováricas/genética , Proteínas Supresoras de Tumor/genética , Vía de Señalización Wnt/genética , Carcinogénesis/genética , Diferenciación Celular , Progresión de la Enfermedad , Epitelio/patología , Trompas Uterinas/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Organoides/patología , Neoplasias Ováricas/patología , Fenotipo , Nicho de Células MadreRESUMEN
Endometrial cancer (EC) is a common gynecological cancer worldwide. Treatment has been improved in recent years; however, in advanced stages, therapeutic options are still limited. The expression of galectins is increased in several tumor types and that they are involved in important cell processes. Large studies on endometrial cancer are still pending; Specimens of 225 patients with EC were immunohistochemically stained with antibodies for Gal-8 and Gal-9. Expression was correlated with histopathological variables. The cytosolic expression of both galectins is associated with grading and survival. Cytosolic Galectin-8 expression is a positive prognostic factor for overall survival (OS) and progression-free survival (PFS), while nuclear Gal-8 expression correlates only to OS. The cytosolic presence of Galectin-9 is correlated with a better prognosis regarding OS. Our results suggest that expression of both galectins is associated with OS and PFS in EC. Further studies are needed to understand the underlying molecular mechanisms.
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Neoplasias Endometriales , Galectinas , Humanos , Galectinas/metabolismo , Galectinas/genética , Femenino , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Neoplasias Endometriales/mortalidad , Persona de Mediana Edad , Anciano , Pronóstico , Biomarcadores de Tumor/metabolismo , Adulto , Anciano de 80 o más Años , InmunohistoquímicaRESUMEN
Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is involved in various eosinophilic diseases. Since increased galectin expression is already detected in the placentas of mothers with gestational diabetes mellitus (GDM), this study focuses on the specific role of galectin-10 and hints at consequences for the diagnosis and therapeutic options of GDM. It is hypothesized that the difference in galectin-10 expression will raise the pathophysiological understanding of gestational diabetes. The study population consists of 80 women: 40 healthy mothers and 40 women suffering from gestational diabetes mellitus. The expression of galectin-10 was analyzed in the syncytiotrophoblast (SCT) and the decidua of the placenta via immunohistochemistry and immunofluorescence double staining. The immunoreactivity score (IRS) was used for evaluation. The results in this study were significant for an overexpression of galectin-10 in GDM placentas compared with the control group. The syncytiotrophoblast showed overexpression in the nucleus and the cytoplasm, whereas expression of galectin-10 in the decidua was significant in the cytoplasm only. This study identified the expression changes in galectin-10 in placental tissue between healthy and GDM mothers and intensified the understanding of gestational diabetes. Assuming that gestational diabetes mellitus is involved in inflammatory processes, galectin-10 might play a role in the development and maintenance of GDM. Further investigation is required to strengthen these findings.
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Cell surface carbohydrate antigens sialyl Lewis X (sLeX) and Lewis Y (LeY) are paramount glycoconjugates and are abundantly expressed in the receptive endometrium. Furthermore, among the important biological functions of both antigens is their role in leukocytes adhesion and extravasation. Interleukin-1 beta (IL-1ß) is involved in the process of human embryo implantation and placenta development. Here, we used an in vitro model to investigate whether sLeX and LeY are playing a role in the embryo implantation process mediated by IL-1ß. Our results are showing that the expression of cell surface sLeX was enhanced in endometrial RL95-2 cells after exposure to IL-1ß. RT-qPCR detection indicated that the transcript level of glycosyltransferase gene fucosyltransferase 3 (FUT3) was significantly elevated and that of FUT4/7 and ST3 beta-galactoside alpha-2,3-sialyltransferase 3/4 (ST3GAL3/4) were decreased by treatment with IL-1ß. Modulatory role of glycosyltransferase FUT3 on sLeX biosynthesis was determined by FUT3 siRNA transfection in RL95-2 cells. Results showed that the expression level of sLeX was suppressed, but no change was observed in regard to LeY. Moreover, IL-1ß promoted the HTR-8/SVneo trophoblast spheroids attachment to the RL95-2 endometrial monolayer, which was partially blocked by anti-sLeX antibody and FUT3 knockdown. Gene expression analysis of the RNA-seq transcriptome data from human secretory endometrium demonstrated a significantly higher level of FUT3 in the mid-secretory phase compared to the early secretory phase, which was correlated with the expression of IL1B. In summary, the inflammatory microenvironment at the fetomaternal interface can regulate the glycosylation pattern of endometrial cells at the time of implantation. SLeX can be significantly induced by IL-1ß via increasing FUT3 expression, which facilitates the trophoblast adhesion during embryo implantation.
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Endometrio , Interleucina-1beta , Trofoblastos , Femenino , Humanos , Embarazo , Adhesión Celular , Implantación del Embrión , Endometrio/metabolismo , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Glicosiltransferasas/metabolismo , Interleucina-1beta/metabolismo , Antígeno Sialil Lewis X/metabolismo , Trofoblastos/metabolismoRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.
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COVID-19 , Gripe Humana , Adulto , Humanos , Enzima Convertidora de Angiotensina 2 , Pulmón/patología , Macrófagos Alveolares/metabolismo , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2 , Tropismo ViralRESUMEN
OBJECTIVE: Because mucinous carcinomas are rare tumors that affect several organ sites and are known to originate from different tissues, leading to frequent misdiagnoses, the objective was to characterize the differences between primary mucinous tumors of the ovary and metastatic mucinous cancer to the ovary by studying the expression pattern of several candidate biomarkers. METHODS: Tissue samples of mucinous histology were obtained between 1985 and 2015. Individual ovary and colon tissue samples were analyzed, including standard (PAX8, CK20, CK7, CDX2, SATB2, estrogen/progesterone) and new (MUC1, MUC5AC) biomarkers, which were then scored for immunoreactivity semi-quantitatively. RESULTS: The study cohort included 98 mucinous tumor samples, including benign mucinous cystadenoma (n=24), mucinous borderline tumors (n=24), mucinous carcinomas (n=40), and metastatic mucinous ovarian carcinomas (n=10). A strong positive correlation was found between PAX8 scoring (p=0.003), CK7 scoring (p=0.0001), and MUC1 scoring (p=0.001) in primary mucinous ovarian cancer. Tumors of increasing invasiveness were analyzed and a significant decrease in the scoring of MUC5AC (p=0.001) was observed, with a stronger expression in adenomas (87%) and borderline tumors (75%), and a lower expression in mucinous cancers (42%). Patients survived significantly longer when their tumors expressed high PAX8 and showed an expansile invasion pattern (p=0.005 and p=0.015, respectively) compared with patients with PAX8-negative tumors and destructive invasion pattern. CONCLUSION: The study data support the diagnostic value of MUC1 as a new biomarker to differentiate between primary and metastatic mucinous ovarian cancer. In addition, the tumor growth pattern along with the PAX8 immunophenotype might represent potential prognostic biomarkers for primary mucinous ovarian carcinomas.
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Adenocarcinoma Mucinoso , Neoplasias Ováricas , Biomarcadores , Carcinoma Epitelial de Ovario , Femenino , Humanos , Mucina 5AC , Mucina-1 , Factor de Transcripción PAX8RESUMEN
BACKGROUND: High-grade serous ovarian cancer (HGSOC) intratumoural vasculature evolution remains unknown. The study investigated changes in tumour microvessel density (MVD) in a large cohort of paired primary and recurrent HGSOC tissue samples and its impact on patients' clinico-pathological outcome. METHODS: A total of 222 primary (pOC) and recurrent (rOC) intra-patient paired HGSOC were assessed for immunohistochemical expression of angiogenesis-associated biomarkers (CD31, to evaluate MVD, and VEGF-A). Expression profiles were compared between pOCs and rOCs and correlated with patients' data. RESULTS: High intratumoural MVD and VEGF-A expression were observed in 75.7% (84/111) and 20.7% (23/111) pOCs, respectively. MVDhigh and VEGF(+) samples were detected in 51.4% (57/111) and 20.7% (23/111) rOCs, respectively. MVDhigh/VEGF(+) co-expression was found in 19.8% (22/111) and 8.1% (9/111) of pOCs and rOCs, respectively (p = 0.02). Pairwise analysis showed no significant change in MVD (p = 0.935) and VEGF-A (p = 0.121) levels from pOCs to rOCs. MVDhigh pOCs were associated with higher CD3(+) (p = 0.029) and CD8(+) (p = 0.013) intratumoural effector TILs, while VEGF(+) samples were most frequently encountered among BRCA-mutated tumours (p = 0.019). Multivariate analysis showed VEGF and MVD were not independent prognostic factors for OS. CONCLUSIONS: HGSOC intratumoural vasculature did not undergo significant changes during disease progression. High concentration of CD31(+) vessels seems to promote recruitment of effector TILs. The study also provides preliminary evidence of the correlation between VEGF-positivity and BRCA status.
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Cistadenocarcinoma Seroso/genética , Neovascularización Patológica/genética , Neoplasias Ováricas/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Proteína BRCA1/genética , Biomarcadores de Tumor/genética , Cistadenocarcinoma Seroso/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Linfocitos Infiltrantes de Tumor/patología , Microvasos/metabolismo , Microvasos/patología , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neovascularización Patológica/patología , Neoplasias Ováricas/patología , Ovario/irrigación sanguínea , Ovario/patologíaRESUMEN
OBJECTIVE: To investigate the association of cancer stem cell biomarker aldehyde dehydrogenase-1 (ALDH1) with ovarian cancer patients' prognosis and clinico-pathological characteristics. METHODS: The electronic searches were performed in January 2018 through the databases PubMed, MEDLINE and Scopus by searching the terms: "ovarian cancer" AND "immunohistochemistry" AND ["aldehyde dehydrogenase-1" OR "ALDH1" OR "cancer stem cell"]. Studies evaluating the impact of ALDH1 expression on ovarian cancer survival and clinico-pathological variables were selected. RESULTS: 233 studies were retrieved. Thirteen studies including 1885 patients met all selection criteria. ALDH1-high expression was found to be significantly associated with poor 5-year OS (ORâ¯=â¯3.46; 95% CI: 1.61-7.42; Pâ¯=â¯0.001, random effects model) and 5-year PFS (ORâ¯=â¯2.14; 95% CI: 1.11-4.13; Pâ¯=â¯0.02, random effects model) in ovarian cancer patients. No correlation between ALDH1 expression and tumor histology (ORâ¯=â¯0.60; 95% CI: 0.36-1.02; Pâ¯=â¯0.06, random effects model), FIGO Stage (ORâ¯=â¯0.65; 95% CI: 0.33-1.30; Pâ¯=â¯0.22, random effects model), tumor grading (ORâ¯=â¯0.76; 95% CI: 0.40-1.45; Pâ¯=â¯0.41, random effects model) lymph nodal status (ORâ¯=â¯2.05; 95% CI: 0.81-5.18; Pâ¯=â¯0.13, random effects model) or patients' age at diagnosis (ORâ¯=â¯0.83; 95% CI: 0.54-1.29; Pâ¯=â¯0.41, fixed effects model) was identified. CONCLUSIONS: Basing on the available evidence, this meta-analysis showed that high levels of ALDH1 expression correlate with worse OS and PFS in ovarian cancer patients.
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Isoenzimas/biosíntesis , Neoplasias Ováricas/enzimología , Retinal-Deshidrogenasa/biosíntesis , Familia de Aldehído Deshidrogenasa 1 , Femenino , Humanos , Isoenzimas/metabolismo , Neoplasias Ováricas/sangre , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Pronóstico , Retinal-Deshidrogenasa/metabolismo , Análisis de SupervivenciaRESUMEN
While the establishment of an ovarian cancer biobank from patient-derived organoids along with their clinical background information promises advances in research and patient care, standardization remains a challenge due to the heterogeneity of this lethal malignancy, combined with the inherent complexity of organoid technology. This adaptable protocol provides a systematic framework to realize the full potential of ovarian cancer organoids considering a patient-specific variability of progenitors. By implementing a structured experimental workflow to select optimal culture conditions and seeding methods, with parallel testing of direct 3D seeding versus a 2D/3D route, we obtain, in most cases, robust long-term expanding lines suitable for a broad range of downstream applications. Notably, the protocol has been tested and proven efficient in a great number of cases (N = 120) of highly heterogeneous starting material, including high-grade and low-grade ovarian cancer and stages of the disease with primary debulking, recurrent disease, and post-neoadjuvant surgical specimens. Within a low Wnt, high BMP exogenous signaling environment, we observed progenitors being differently susceptible to the activation of the Heregulin 1 ß (HERß-1)-pathway, with HERß-1 promoting organoid formation in some while inhibiting it in others. For a subset of the patient's samples, optimal organoid formation and long-term growth necessitate the addition of fibroblast growth factor 10 and R-Spondin 1 to the medium. Further, we highlight the critical steps of tissue digestion and progenitor isolation and point to examples where brief cultivation in 2D on plastic is beneficial for subsequent organoid formation in the Basement Membrane Extract type 2 matrix. Overall, optimal biobanking requires systematic testing of all main conditions in parallel to identify an adequate growth environment for individual lines. The protocol also describes the handling procedure for efficient embedding, sectioning, and staining to obtain high-resolution images of organoids, which is required for comprehensive phenotyping.
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Bancos de Muestras Biológicas , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Organoides/metabolismoRESUMEN
OBJECTIVES: Gestational diabetes mellitus (GDM) is a growing health concern. Since members of the galectin-family are identified to play a role in the pathogenesis of GDM, we determined galectin-12 as an essential protein due to its influence in lipolysis and inflammation processes. This study investigates the expression of galectin-12 in the placentas of women with GDM. STUDY DESIGN: The study population includes 40 expectant women suffering from GDM and 40 healthy controls. The expression of galectin-12 in the syncytiotrophoblast (SCT) and the extra villous trophoblast (EVT) of the placenta was analyzed by immunohistological staining and double immunofluorescence. Immunoreactivity Score (IRS) was used for evaluation. RESULTS: The results demonstrate a significant overexpression of galectin-12 in the nucleus of the SCT and the EVT of placentas with GDM compared to the healthy control group. Additionally, double immunofluorescence visualizes corresponding results with an overexpression of galectin-12 in the extra villous trophoblast of GDM placentas representing maternal cells. CONCLUSION: This study identifies galectin-12 to be associated with the process of gestational diabetes mellitus. These findings are in correspondence with the involvement of galectin-12 in inflammatory processes. Maternal BMI and male sex seem to be confounder for the expression of galectin-12 in the nuclear syncytiotrophoblast, but not in other parts of the investigated placental areas. Further investigations are necessary to verify the correlation between gestational diabetes mellitus and the expression of galectin-12 in the placenta and to further elucidate its distinct role.
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Diabetes Gestacional , Galectinas , Placenta , Trofoblastos , Adulto , Femenino , Humanos , Masculino , Embarazo , Diabetes Gestacional/inmunología , Diabetes Gestacional/metabolismo , Galectinas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Placenta/metabolismo , Placenta/inmunología , Placenta/patología , Trofoblastos/metabolismo , Trofoblastos/patología , Trofoblastos/inmunologíaRESUMEN
The obligate intracellular pathogen Chlamydia trachomatis (Ctr) is a major cause of sexually transmitted disease and infertility worldwide. Ascending genital infections cause inflammation of fallopian tubes and subsequent scarring and occlusion. The cellular basis for such sequelae remains undetermined. We used confocal immunofluorescence microscopy to show that Ctr disrupts epithelial homeostasis in an ex vivo infection model of human fallopian tubes. Ctr triggered loss of polarity of inclusion harboring cells and of neighboring uninfected cells, as shown by subcellular redistribution of adhesion and polarity (occludin) markers. ß-catenin (a component of the adherens junction and a Wnt signaling transducer) was recruited to the bacterial inclusion, suggesting a role for Wnt signaling in Ctr-mediated tissue damage. Comparative microarray analysis of infected epithelium in the presence of the Wnt secretion inhibitor (IWP2) demonstrated that the transcriptional response to Ctr infection was highly dependent on active Wnt secretion, moreover IWP2 reversed Ctr-induced tissue phenotypes. Notably, we observed the up-regulation of differentiation and proliferation biomarkers olfactomedin 4 and epithelial cell adhesion molecule, and also Ctr-induced proteolytic activation of epithelial cell adhesion molecule. Thus, acute Ctr infection activates the paracrine Wnt signaling pathway, leading to profound disruption of epithelial structure and function that facilitates the dissemination of damage beyond that of infected cells.
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Infecciones por Chlamydia/fisiopatología , Chlamydia trachomatis/fisiología , Enfermedades de las Trompas Uterinas/fisiopatología , Homeostasis/fisiología , Comunicación Paracrina/fisiología , Vía de Señalización Wnt/fisiología , Antígenos de Neoplasias/metabolismo , Adhesión Celular/fisiología , Moléculas de Adhesión Celular/metabolismo , Polaridad Celular/fisiología , Molécula de Adhesión Celular Epitelial , Células Epiteliales/microbiología , Células Epiteliales/fisiología , Enfermedades de las Trompas Uterinas/microbiología , Trompas Uterinas/microbiología , Trompas Uterinas/fisiopatología , Femenino , Humanos , Regulación hacia Arriba , beta Catenina/metabolismoRESUMEN
High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies.
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Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Dermatoglifia del ADN , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Femenino , Humanos , Mutación/genética , Clasificación del TumorRESUMEN
We present a protocol for effective biobanking of epithelial ovarian cancer organoids, considering the heterogeneous clinical presentation and high recurrence rates. Our protocol involves parallel testing of three media to identify patient-specific optimal conditions. We describe steps for tissue dissociation, differential seeding, organoid cultivation, and biobanking. We outline procedures for fixation, embedding, and staining for confocal imaging. Furthermore, we demonstrate that brief cultivation of isolates in 2D on plastic enhances organoid-forming potential in selected lines, expanding their application scope. For complete details on the use and execution of this protocol, please refer to Hoffmann et al.1.
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Bancos de Muestras Biológicas , Neoplasias Ováricas , Humanos , Femenino , Técnicas Histológicas , Organoides , Coloración y EtiquetadoRESUMEN
BACKGROUND: Tumour heterogeneity in high-grade serous ovarian cancer (HGSOC) is a proposed cause of acquired resistance to treatment and high rates of relapse. Among the four distinct molecular subtypes of HGSOC, the mesenchymal subtype (MES) has been observed with high frequency in several study cohorts. Moreover, it exhibits aggressive characteristics with poor prognosis. The failure to adequately exploit such subtypes for treatment results in high mortality rates, highlighting the need for effective targeted therapeutic strategies that follow the idea of personalized medicine (PM). METHODS: As a proof-of-concept, bulk and single-cell RNA data were used to characterize the distinct composition of the tumour microenvironment (TME), as well as the cell-cell communication and its effects on downstream transcription of MES. Moreover, transcription factor activity contextualized with causal inference analysis identified novel therapeutic targets with potential causal impact on transcription factor dysregulation promoting the malignant phenotype. FINDINGS: Fibroblast and macrophage phenotypes are of utmost importance for the complex intercellular crosstalk of MES. Specifically, tumour-associated macrophages were identified as the source of interleukin 1 beta (IL1B), a signalling molecule with significant impact on downstream transcription in tumour cells. Likewise, signalling molecules tumour necrosis factor (TNF), transforming growth factor beta (TGFB1), and C-X-C motif chemokine 12 (CXCL12) were prominent drivers of downstream gene expression associated with multiple cancer hallmarks. Furthermore, several consistently hyperactivated transcription factors were identified as potential sources for treatment opportunities. Finally, causal inference analysis identified Yes-associated protein 1 (YAP1) and Nuclear Receptor Subfamily 2 Group F Member 6 (NR2F6) as novel therapeutic targets in MES, verified in an independent dataset. INTERPRETATION: By utilizing a sophisticated bioinformatics approach, several candidates for treatment opportunities, including YAP1 and NR2F6 were identified. These candidates represent signalling regulators within the cellular network of the MES. Hence, further studies to confirm these candidates as potential targeted therapies in PM are warranted.
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PURPOSE: Endometrial cancer is the most common gynecological malignancy. The helicase RIG-I, a part of the innate immune system, and EFTUD2, a splicing factor which can upregulate RIG-I expression, are shown to influence tumor growth and disease progression in several malignancies. For endometrial cancer, an immunogenic cancer, data about RIG-I and EFTUD2 are still missing. The aim of this study was to examine the expression of RIG-I and EFTUD2 in endometrial cancer. METHODS: 225 specimen of endometrial cancer were immunohistochemically stained for RIG-I and EFTUD2. The results were correlated to clinicopathological data, overall survival (OS) and progression-free survival (PFS). RESULTS: High RIG-I expression correlated with advanced tumor stages (FIGO: p = 0.027; pT: p = 0.010) and worse survival rates (OS: p = 0.009; PFS: p = 0.022). High EFTUD2 expression correlated to worse survival rates (OS: p = 0.026; PFS: p < 0.001) and was determined to be an independent marker for progression-free survival. CONCLUSION: Our data suggest that the expression of RIG-I and EFTUD2 correlates with survival data, which makes both a possible therapeutic target in the future.
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Neoplasias Endometriales , Femenino , Humanos , Estadificación de Neoplasias , Neoplasias Endometriales/patología , Pronóstico , Factores de Elongación de Péptidos , Ribonucleoproteína Nuclear Pequeña U5RESUMEN
PURPOSE: An increasing infiltration of FoxP3-positive T-regs is associated with a higher grade of cervical intraepithelial neoplasia. The T-reg-recruiting chemokine CCL22 is expressed in various tumour entities. Aim of our study was to investigate the role of CCL22 in the progression and regression of cervical intraepithelial neoplasias, especially in patients with intermediate cervical intraepithelial neoplasias (CIN II). Furthermore, our aim was to characterize the CCL22-producing cells and explore the role of innate immunity in the process of cells recruitment. METHODS: CCL22 expression was analyzed immunohistochemically in 169 patient samples. The immunoreactive score as well as the median numbers of positive cells were calculated in each slide and correlated with the histological CIN grade and FoxP3 expression. Additionally, CD68/CCL22 as well as CD68/PPARγ and CD68/FoxP3 expression were examined by double immunofluorescence. Statistical analysis was performed by SPSS 26. RESULTS: A significantly higher expression of epithelial CCL22 in CIN II with progression in comparison to CIN II with regression (p = 0.006) could be detected. CCL22 was correlated with FoxP3 (Spearman's Rho: 0.308; p < 0.01). In 88%, CCL22-positive cells were positive for CD68, and 71% of CD68-positive macrophages expressed PPARγ. Colocalization of CD68 and FoxP3 was detected in 12%. CONCLUSION: We could demonstrate that increased expression of CCL22, mainly produced by macrophages, correlates with elevated potential of malignancy. CCL22 expression could act as a predictor for regression and progression in cervical intraepithelial neoplasia, and it may help in the decision process regarding surgical treatment versus watchful waiting strategy in order to prevent conisation-associated risks. Furthermore, our findings support the potential of CCL22-producing cells as a target for immune therapy in cervical cancer patients.
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Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Quimiocina CCL22/metabolismo , PPAR gamma , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/patología , Factores de Transcripción Forkhead/metabolismoRESUMEN
There exists a variety of studies about tumor-infiltrating immune cells (TIICs) in cervical cancer, but their prognostic value in correlation with the histopathological subtype has never been investigated. Therefore, the aim of this study was to quantify TIICs in a panel of 238 sporadic cervical cancers and investigate the correlation with cervical cancer subtype and patient survival. TIICs levels were significantly increased in the subgroup of CSCC (191 samples) in comparison to CAC (47 samples). In CSCC, TIICs' infiltration showed a negative correlation with age, FIGO stage and with the histone protein modification H3K4me3. Moreover, in CAC, it was positively correlated with p16 and with the glucocorticoid receptor and inversely correlated with the MDM2 protein and with H3K4me3. Interestingly, immune infiltration was an independent positive prognosticator for disease-free survival (DFS) in patients with CSCC, those bearing tumors with the strongest TIICs infiltration showing the better DFS. Altogether, the present study provides a differentiated overview of the relations between TIIC levels and prognosis in patients with CSCC vs. patients with CAC.
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The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRα, TRα1, and TRα2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRα and the α1 and α2 isoforms were evaluated via immuno-histochemistry. Prognosis-determining aspects were calculated via univariate, as well as multivariate, analysis. Univariate Cox-regression analysis revealed no association between nuclear TRα expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRα expression was significantly correlated with a poor outcome for both OS (p = 0.034) and ten-year survival (p = 0.009). Strengthening these results, cytoplasmic TRα was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRα-subgroups revealed that TRα1 had no prognostic relevance, whereas nuclear TRα2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRα2 expression was found to be an independent positive prognosticator (p = 0.030) when adjusted to fit clinico-pathological parameters. Overall, our results support the hypothesis that subcellular localization of TRα and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRα expression correlates with more aggressive disease progression, whereas nuclear TRα2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.
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Placental macrophages are highly heterogeneous cells with differential phenotypes and functions defined by differential origins and modulated by the changing placental environment. During pregnancy, placental macrophages play a critical role in embryo implantation, placenta formation and homeostasis, fetal development and parturition. This review summarizes recent findings on the cellular origin of placental macrophages, and provide a comprehensive description of their phenotypes, corresponding molecular markers and functions in human placenta. Finally, alterations of placental macrophages in pregnancy-related diseases are discussed.
Asunto(s)
Placenta , Complicaciones del Embarazo , Embarazo , Femenino , Humanos , Macrófagos , Parto , Biomarcadores , Desarrollo FetalRESUMEN
BACKGROUND: The therapy concepts that target several members of krüppel like factor (KLF) family have been achieved in breast cancer (BC). However, the role of KLF11 in BC remains unclear. This study explored the prognostic significance of KLF11 in BC patients and investigated its functional roles in this malignancy. METHODS: Immunohistochemistry (IHC) staining of KLF11 in 298 patients' samples was performed to determine the prognostic role of the KLF11. Then the protein level was correlated to clinicopathological characteristics and survival outcomes. Afterward, the function of KLF11 was explored in vitro with siRNA-mediated loss-of-function of cell viability, proliferation, and apoptosis. RESULTS: From the cohort study, we found that the expression of KLF11 was positively associated with highly proliferative BC of BC. Furthermore, prognostic analysis demonstrated that KLF11 was an independent negative factor for disease-free survival (DFS) and distant-metastasis-free survival (DMFS) of BC. The KLF11-related prognostic model for DFS and DMFS showed high accuracy in predicting the 3-,5- and 10 -year survival probability of BC patients. Additionally, the knockdown of KLF11 inhibited cell viability and proliferation, as well as induced cell apoptosis in MCF7 and MDA-MB-231 cells, while only inhibited cell viability and induced cell apoptosis in SK-BR-3 cells. CONCLUSIONS: Our study indicated that targeting KLF11 is an interesting therapeutic concept and further research could lead to a new therapeutic improvement in BC, especially in highly aggressive molecular subtypes.