scholarly journals Autophagy Process in Trophoblast Cells Invasion and Differentiation: Similitude and Differences With Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Lorena Carvajal ◽  
Jaime Gutiérrez ◽  
Eugenia Morselli ◽  
Andrea Leiva
Keyword(s):  
Cancer Cells ◽  
Vascular Remodeling ◽  
Cell Types ◽  
Cellular Adhesion ◽  
Tumor Promoter ◽  
Extravillous Trophoblast ◽  
Trophoblast Cells ◽  
Placental Development ◽  
Placental Perfusion ◽  
Blastocyst Implantation

Early human placental development begins with blastocyst implantation, then the trophoblast differentiates and originates the cells required for a proper fetal nutrition and placental implantation. Among them, extravillous trophoblast corresponds to a non-proliferating trophoblast highly invasive that allows the vascular remodeling which is essential for appropriate placental perfusion and to maintain the adequate fetal growth. This process involves different placental cell types as well as molecules that allow cell growth, cellular adhesion, tissular remodeling, and immune tolerance. Remarkably, some of the cellular processes required for proper placentation are common between placental and cancer cells to finally support tumor growth. Indeed, as in placentation trophoblasts invade and migrate, cancer cells invade and migrate to promote tumor metastasis. However, while these processes respond to a controlled program in trophoblasts, in cancer cells this regulation is lost. Interestingly, it has been shown that autophagy, a process responsible for the degradation of damaged proteins and organelles to maintain cellular homeostasis, is required for invasion of trophoblast cells and for vascular remodeling during placentation. In cancer cells, autophagy has a dual role, as it has been shown both as tumor promoter and inhibitor, depending on the stage and tumor considered. In this review, we summarized the similarities and differences between trophoblast cell invasion and cancer cell metastasis specifically evaluating the role of autophagy in both processes.

scholarly journals Could the Human Endogenous Retrovirus-Derived Syncytialization Inhibitor, Suppressyn, Limit Heterotypic Cell Fusion Events in the Decidua?

2021 ◽  
Vol 22 (19) ◽  
pp. 10259
Author(s):  
Jun Sugimoto ◽  
Sehee Choi ◽  
Megan Sheridan ◽  
Iemasa Koh ◽  
Yoshiki Kudo ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Cell Types ◽  
Trophoblast Cell ◽  
Endogenous Retroviruses ◽  
Extravillous Trophoblast ◽  
Human Endogenous Retrovirus ◽  
Decidual Cell ◽  
Placental Development ◽  
Adverse Pregnancy ◽  
Herv Expression

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes.

scholarly journals Functional Evaluation of STOX1 (STORKHEAD-BOX PROTEIN 1) in Placentation, Preeclampsia, and Preterm Birth

Hypertension ◽  
2020 ◽  
Author(s):  
Caroline E. Dunk ◽  
Marie van Dijk ◽  
Ruhul Choudhury ◽  
Thomas J. Wright ◽  
Brian Cox ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Vascular Remodeling ◽  
Killer Cell ◽  
Extravillous Trophoblast ◽  
Functional Evaluation ◽  
Wild Type ◽  
Placental Development ◽  
Monocyte Migration ◽  
Il Interleukin ◽  
Early Onset Preeclampsia

Revaluation of the association of the STOX1 (STORKHEAD_BOX1 PROTEIN 1) transcription factor mutation (Y153H, C allele) with the early utero-vascular origins of placental pathology is warranted. To investigate if placental STOX1 Y153H genotype affects utero-vascular remodeling—compromised in both preterm birth and preeclampsia—we utilized extravillous trophoblast (EVT) explant and placental decidual coculture models, transfection of STOX1 wild-type and mutant plasmids into EVT-like trophoblast cell lines, and a cohort of 75 placentas from obstetric pathologies. Primary EVT and HTR8/SVneo cells carrying STOX1 Y153H secreted lower levels of IL (interleukin) 6, and IL-8, and higher CXCL16 (chemokine [C-X-C motif] ligand 16) and TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) than wild-type EVT and Swan71 cells. Media from wild-type EVT or Swan71 cells transfected with wild-type STOX1 stimulated: endothelial chemokine expression, angiogenesis, and decidual natural killer cell and monocyte migration. In contrast, Y153H EVT conditioned medium, Swan71 transfected with the Y153H plasmid, or HTR8/SVneo media had no effect. Genotyping of placental decidual cocultures demonstrated association of the placental STOX1 CC allele with failed vascular remodeling. Decidual GG NODAL R165H increased in failed cocultures carrying the placental CC alleles of STOX1. Multivariate analysis of the placental cohort showed that the STOX1 C allele correlated with premature birth, with or without severe early-onset preeclampsia, and small for gestational age babies. In conclusion, placental STOX1 Y153H is a precipitating factor in preterm birth and placental preeclampsia due to defects in early utero-placental development.

scholarly journals Regulation of the Matricellular Proteins CYR61 (CCN1) and NOV (CCN3) by Hypoxia-Inducible Factor-1α and Transforming-Growth Factor-β3 in the Human Trophoblast

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2835-2845 ◽  
Author(s):  
Nadine Wolf ◽  
Wei Yang ◽  
Caroline E. Dunk ◽  
Isabella Gashaw ◽  
Stephen J. Lye ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Extravillous Trophoblast ◽  
Migration And Invasion ◽  
Ccn Proteins ◽  
Low Oxygen ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Placental Perfusion ◽  
Hypoxia Inducible Factor 1Α ◽  
Trophoblast Migration

It is known that a hypoxic environment is critical for trophoblast migration and invasion and is fundamental for appropriate placental perfusion. Because cysteine-rich 61 (CYR61, CCN1) and nephroblastoma overexpressed (NOV, CCN3) are expressed in the extravillous trophoblast and expression levels are deregulated in preeclampsia, we investigated their regulation properties in first-trimester placental explants and in JEG3 choriocarcinoma cells upon a physiological low oxygen tension of 1–3%. In placental explants, both proteins were expressed in the extravillous trophoblast cells and were increased upon hypoxia. JEG3 cells revealed a significant up-regulation of CYR61 and NOV intracellular as well as secreted protein upon hypoxic treatment accompanied by the stabilization of the hypoxia-inducible factor-1α (HIF-1α). Treatment with dimethyloxalylglycine to mimic hypoxia and silencing of HIF-1α using small interfering RNA revealed that only the increase in intracellular protein expression seems to be dependent on HIF-1α but obviously not the secretion process. Moreover, recombinant TGF-β3 was able to further enhance the amount of intracellular CCN proteins as well as secreted CYR61 levels under hypoxia. These results indicate that low oxygen levels trigger elevation of intracellular as well as secreted CYR61 and NOV protein probably in two independent pathways. Addition of recombinant CYR61 and NOV proteins increases migration as well as invasion properties of JEG3 trophoblast cells, which strengthen their role in supporting trophoblast migration invasion properties. In summary, CYR61 and NOV are regulated by HIF-1α and TGF-β3 in the trophoblast cell line JEG3, and their enhanced secretion could be implicated in appropriate placental invasion.

scholarly journals Galectin-9 regulates HTR8/SVneo function via JNK signaling

Reproduction ◽  
2021 ◽  
Vol 161 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Mengdie Li ◽  
Xiandong Peng ◽  
Jinfeng Qian ◽  
Fengrun Sun ◽  
Chunqin Chen ◽  
...  
Keyword(s):  
Umbilical Vein ◽  
First Trimester ◽  
Normal Pregnancy ◽  
Extravillous Trophoblast ◽  
Functional Study ◽  
Dependent Manner ◽  
Trophoblast Cells ◽  
Placental Perfusion ◽  
Jnk Signaling ◽  
Umbilical Vein Endothelial Cells

To obtain a successful pregnancy, trophoblasts must provide a physical barrier, suppress maternal reactivity, produce immunosuppressive hormones locally, and enhance the production of blocking factors that are able to bind to several antigenic sites. Inadequate placental perfusion has been closely associated with several pregnancy-associated diseases. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation. We utilized immortalized human first-trimester extravillous trophoblast cells (HTR8/SVneo) for our functional study and examined the effects of Gal-9 on apoptosis, cytokine production and angiogenesis of HTR8/SVneo cells. Gal-9 inhibited the apoptosis and IFN-γ and IL-17A production, promoted IL-4 production, and coordinated the crosstalk between HTR8/SVneo cells and human umbilical vein endothelial cells via its interaction with Tim-3. Blockade of JNK signaling inhibited Gal-9 activities in HTR8/SVneo cells. In addition, we detected a correlation between low levels of Gal-9 and spontaneous abortion. So Gal-9 could inhibit the apoptosis and proinflammatory cytokine expression, and promote the angiogenesis and IL-4 production in HTR8/SVneo cells via Tim-3 in a JNK dependent manner to help the maintenance of normal pregnancy. These findings possibly identify Gal-9 as a key regulator of trophoblast cells and suggest its potential as a biomarker and target for the treatment of recurrent pregnancy loss.

scholarly journals The Possible Role of Extravillous Trophoblast-Derived Exosomes on the Uterine Spiral Arterial Remodeling under Both Normal and Pathological Conditions

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Carlos Salomon ◽  
Sarah W. Yee ◽  
Murray D. Mitchell ◽  
Gregory E. Rice
Keyword(s):  
Vascular Remodeling ◽  
Biological Fluids ◽  
Cell Communication ◽  
Subsequent Development ◽  
Extravillous Trophoblast ◽  
Trophoblast Cells ◽  
Site Of Action ◽  
Local Cell ◽  
Poor Pregnancy Outcome

A tenet of contemporary obstetrics is that events that compromise placentation increase the risk of complications of pregnancy and contribute to poor pregnancy outcome. In particular, conditions that affect the invasion of placental cells and remodeling of uterine spiral arteries compromise placental function and the subsequent development of the fetus. Extravillous trophoblast cells (EVTs) proliferate and migrate from the cytotrophoblast in the anchoring villi of the placenta and invade the maternal decidua and myometrium. These cells are localised with uterine uterine spiral arteries and are thought to induce vascular remodeling. A newly identified pathway by which EVTs may regulate vascular remodeling within the uterus is via the release of exosomes. Trophoblast cells release exosomes that mediate aspects of cell-to-cell communication. The aim of this brief commentary is to review the putative role of exosomes released from extravillous trophoblast cells in uterine spiral artery remodeling and, in particular, their role in the aetiology of preeclampsia. Placental exosomes may engage in local cell-to-cell communication between the cell constituents of the placenta and contiguous maternal tissues and/or distal interactions, involving the release of placental exosomes into biological fluids and their transport to a remote site of action.

Morphological features of endo- and myometrium in patients with uterine leiomyoma and infertility

2020 ◽  
pp. 33-37
Author(s):  
M.A. Flaksenberg ◽  
◽  
Keyword(s):  
Uterine Leiomyoma ◽  
Negative Impact ◽  
Reproductive Function ◽  
Cell Types ◽  
Underlying Disease ◽  
Reproductive Organs ◽  
Pathological Process ◽  
Simple Type ◽  
Morphological Examination ◽  
Blastocyst Implantation

The objective: determination of morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility to restore reproductive function and prevent recurrence of the underlying disease. Materials and methods. In order to restore reproductive function and prevent recurrence of the underlying disease, morphofunctional features of leiomatous nodes and endometrium in women with uterine leiomyoma and infertility were determined. Thirty samples of leiomyomatous nodes and endometrium were examined, among which 15 were obtained from women with multiple uterine leiomyoma and infertility and 15 samples from women with uterine leiomyoma with isolated uterine leiomyoma. During the study, a general-histological method was used for staining with hematoxylin-eosin and picrofuxin by van Gizon, as well as immunohistochemical methods. Histological examination of the endometrium was performed according to conventional protocol, taking into account the day of the menstrual cycle and R.W. Noyes criteria. Results. In the morphological examination of leiomyomatous nodes in the vast majority of cases the presence of uterine leiomyomas of simple and cell types or their combination was established. In women with multiple uterine leiomyoma, simple-type leiomyoma (53.3%) was predominant, and in patients with isolated leiomyoma the signs of cellular uterine leiomyoma (66.7%) were more frequently found. In 80.0% of women with uterine leiomyoma revealed pathology of the endometrium, such as glandular and glandular-fibrous polyps, simple and complex atypical endometrial hyperplasia, which confirms the theory about the only pathogenetic mechanisms of the emergence of hyperplastic processes of female organs. In 66.7% of women with multiple leiomyomas, signs of chronic endometritis have been found, which exacerbates the pathological process and can have a negative impact on the reproductive function, such as secretory endometrial transformation and impaired blastocyst implantation, and explains a much higher percentage of infertility in the group. Conclusion. In women with impaired reproductive function, patients with uterine leiomyoma, it is necessary to conduct a study of the receptivity of the reproductive organs, namely - the endometrium and leiomatous nodes. This will make it possible to use one or another method of treatment in order to restore reproductive function and prevent recurrence of the underlying disease. Keywords: infertility, uterine leiomyoma, endometrium, receptive apparatus.

scholarly journals The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

2021 ◽  
Vol 22 (9) ◽  
pp. 4960
Author(s):  
Natalia Guillén Díaz-Maroto ◽  
Gemma Garcia-Vicién ◽  
Giovanna Polcaro ◽  
María Bañuls ◽  
Nerea Albert ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Colorectal Tumor ◽  
Cytotoxic Drugs ◽  
Differential Sensitivity ◽  
Paracrine Signaling ◽  
Inflammatory Phenotype ◽  
Heterotypic Interactions ◽  
Carcinoma Associated Fibroblasts

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

scholarly journals Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1877
Author(s):  
Gilles Lalmanach ◽  
Mariana Kasabova-Arjomand ◽  
Fabien Lecaille ◽  
Ahlame Saidi
Keyword(s):  
Prognostic Significance ◽  
Tight Binding ◽  
Cysteine Protease Inhibitor ◽  
Tumor Promoter ◽  
Regulatory Mechanisms ◽  
Placental Development ◽  
Cysteine Cathepsins ◽  
Cystatin M

Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the CST6 promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer.

Expression of interleukin-6 (IL-6), signal transducer and activator of transcription-3 (STAT-3) and telomerase in choriocarcinomas

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Luciana Pietro ◽  
Fátima Bottcher-Luiz ◽  
Lício Augusto Velloso ◽  
Joseane Morari ◽  
Marcelo Nomura ◽  
...  
Keyword(s):  
Cell Transformation ◽  
First Trimester ◽  
Bewo Cell ◽  
Placental Development ◽  
Trimester Abortion ◽  
Bewo Cells ◽  
Culture Cells ◽  
Bewo Cell Line ◽  
Blastocyst Implantation ◽  
First Trimester Of Pregnancy

Abstract Blastocyst implantation and neoplastic invasion have some common properties related to tissue invasion, mediated by various cytokines. Aim To compare the expression of IL-6, STAT-3 and telomerase in material of abortions in the first trimester of pregnancy, at term placentas and in choriocarcinomas. Methods Immunohistochemical reactions were performed on formalin fixed and included in paraffin samples from 3 groups: abortions, normal at term placentas and choriocarcinomas. Western Blot and Real-Time PCR assays were performed on fresh material from BeWo cell line and in primary culture cells of normal placenta. Results Immunohistochemical reactions: IL-6 expression was moderate in the first trimester abortion samples and high in at term placentas and choriocarcinomas. STAT-3 was strongly positive in all groups. Telomerase expression was absent in normal at term placentas but was increased in BeWo cells. Conclusion IL-6 and STAT-3 are present in the invasion process of the normal placental development and they are maintained during the malignant transformation to choriocarcinoma. The intense telomerase expression observed in BeWo cells was strongly associated with the malignant phenotype, confirming it as a good marker for cell transformation and tumor progression.

scholarly journals Modelling the Human Placental Interface In Vitro—A Review

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 884
Author(s):  
Marta Cherubini ◽  
Scott Erickson ◽  
Kristina Haase
Keyword(s):  
Drug Testing ◽  
Cell Types ◽  
In Vitro Models ◽  
Placental Development ◽  
Scientific Challenge ◽  
Induced Pluripotent ◽  
And Function ◽  
And Control

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal–fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

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