Oxygen as a regulator of cellular phenotypes in pregnancy and cancer

2002 ◽  
Vol 80 (2) ◽  
pp. 103-109 ◽  
Author(s):  
Gendie E Lash ◽  
Lynne-Marie Postovit ◽  
Nicola E Matthews ◽  
Eugene Y Chung ◽  
Matthew T Canning ◽  
...  
Keyword(s):  
Tumour Progression ◽  
Antitumour Activity ◽  
Trophoblast Invasion ◽  
Cellular Phenotype ◽  
Low Oxygen ◽  
Microenvironmental Factors ◽  
Blastocyst Implantation ◽  
Cellular Behaviour ◽  
Cellular Phenotypes ◽  
Oxygenation Status

Cellular phenotype is determined by genetic and microenvironmental factors. There is evidence that tissue oxygenation status is one of the microenvironmental factors regulating cellular behaviour. Both normal and pathological processes such as blastocyst implantation in the uterus, placentation, and rapidly growing tumours occur under conditions characterized by relatively low oxygen levels. In this review, we address the effects of low oxygen concentrations on the phenotype of trophoblast and cancer cells. We provide evidence that oxygenation levels play an important role in the regulation of normal and pathological cellular invasiveness as it occurs during trophoblast invasion of the uterus and in tumour progression and metastasis, drug resistance in cancer, and antitumour activity of natural killer cells of the immune system.Key words: hypoxia, pregnancy, cancer.

scholarly journals Prostaglandins and the initiation of blastocyst implantation and decidualization

Reproduction ◽  
2007 ◽  
Vol 134 (5) ◽  
pp. 635-643 ◽  
Author(s):  
Thomas G Kennedy ◽  
Carolina Gillio-Meina ◽  
Sen Han Phang
Keyword(s):  
Vascular Permeability ◽  
Trophoblast Invasion ◽  
Considerable Evidence ◽  
Blastocyst Implantation

The process of blastocyst implantation in mammals is remarkably variable, especially in the extent of trophoblast invasion of the endometrium. In most species studied, the earliest macroscopically identifiable sign of blastocyst implantation is an increase in endometrial vascular permeability in areas adjacent to the blastocysts. This is followed in species with invasive implantation by decidualization, again localized to areas adjacent to the blastocysts. In some species, the application of a stimulus to the endometrium can result in increased endometrial vascular permeability and decidualization. Based initially on studies utilizing inhibitors of prostaglandin (PG) synthesis and more recently on studies using the techniques of transgenics, considerable evidence has accumulated indicating that PGs have an important role in the early events of implantation and artificially induced decidualization. However, which PGs are involved remains controversial. There may be differences between species, and different PGs may be involved at different times.

scholarly journals New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Daniela P. Foti ◽  
Francesco Paonessa ◽  
Eusebio Chiefari ◽  
Antonio Brunetti
Keyword(s):  
Insulin Receptor ◽  
Target Genes ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Peptide Hormone ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Preclinical Research ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

scholarly journals The role of NDRG1 in the pathology and potential treatment of human cancers

2013 ◽  
Vol 66 (11) ◽  
pp. 911-917 ◽  
Author(s):  
Dong-Hun Bae ◽  
Patric J Jansson ◽  
Michael L Huang ◽  
Zaklina Kovacevic ◽  
Danuta Kalinowski ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Anticancer Agents ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Primary Tumour ◽  
Normal Tissues ◽  
Human Cancers ◽  
Physiological Processes ◽  
Cancer Pathology

N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents.

scholarly journals Diverse Roles of Prostaglandins in Blastocyst Implantation

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Naguib Salleh
Keyword(s):  
Growth And Development ◽  
Embryo Implantation ◽  
Trophoblast Invasion ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Broad Perspective ◽  
Blastocyst Implantation ◽  
Embryo Transport ◽  
Derivatives Of

Prostaglandins (PGs), derivatives of arachidonic acid, play an indispensable role in embryo implantation. PGs have been reported to participate in the increase in vascular permeability, stromal decidualization, blastocyst growth and development, leukocyte recruitment, embryo transport, trophoblast invasion, and extracellular matrix remodeling during implantation. Deranged PGs syntheses and actions will result in implantation failure. This review summarizes up-to-date literatures on the role of PGs in blastocyst implantation which could provide a broad perspective to guide further research in this field.

scholarly journals Correlation of Ferritine and Brain Derived Neurotrophic Factor (BDNF) Levels in Preeclampsia

2021 ◽  
Vol 5 (2) ◽  
pp. 161-177
Author(s):  
Dona Mirsa Putri ◽  
Ariadi Ariadi ◽  
Yusrawati Yusrawati
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Neurotrophic Factor ◽  
Serum Levels ◽  
Brain Derived Neurotrophic Factor ◽  
Trophoblast Invasion ◽  
Deficiency Anemia ◽  
Placental Development ◽  
Blastocyst Implantation ◽  
Metalloproteinase 9

Iron deficiency anemia that followed by low serum ferritin levels in early pregnancy has an indirect impact on decreasing the expression of Brain Derived Neurotrophic Factor (BDNF) in the maternal hippocampus. BDNF together with its receptor tyrosine kinase B (TrkB) induced the expression of metalloproteinase-9 (MMP-9) which plays an important role in blastocyst implantation, trophoblast invasion and placental development. Decreasing BDNF levels can interfere with those process which caused imbalance of pro-angiogenic and anti-angiogenic factors such as VEGF, PIGF, sFlt1 and sEng that leads to preeclampsia. This study aims to determine the correlation between ferritin and BDNF serum levels in preeclampsia.Keywords: Preeclampsia, ferritin, iron deficiency anemia, Brain Derived Neurotrophic Factor

scholarly journals Material-Driven Fibronectin Assembly Rescues Matrix Defects due to Mutations in Collagen IV in Fibroblasts

2020 ◽  
Author(s):  
Elie Ngandu Mpoyi ◽  
Marco Cantini ◽  
Yuan Yan Sin ◽  
Lauren Fleming ◽  
Dennis W. Zhou ◽  
...  
Keyword(s):  
Ethyl Acrylate ◽  
Collagen Iv ◽  
Basement Membranes ◽  
Cellular Phenotype ◽  
Structural Support ◽  
The Matrix ◽  
Primary Fibroblasts ◽  
Cellular Phenotypes ◽  
Fibronectin Assembly ◽  
Shed Light

AbstractBasement membranes (BMs) provide structural support to tissues and influence cell signaling. Mutations in COL4A1/COL4A2, a major BM component, cause eye, kidney and cerebrovascular disease, including stroke. Common variants in these genes are risk factors for intracerebral hemorrhage in the general population. However, the contribution of the matrix to the disease mechanism(s) and its effects on the biology of cells harboring a collagen IV mutation remain poorly understood. To shed light on this, we engineered controlled microenvironments using polymer biointerfaces coated with ECM proteins laminin or fibronectin (FN), to investigate the cellular phenotype of primary fibroblasts harboring a COL4A2+/G702D mutation. FN nanonetworks assembled on poly(ethyl acrylate) (PEA) induced increased deposition and assembly of collagen IV in COL4A2+/G702D cells, which was associated with reduced ER size and enhanced levels of protein chaperones such as BIP, suggesting increased protein folding capacity of cells. FN nanonetworks on PEA also partially rescued the reduced stiffness of the deposited matrix and cells, and enhanced cell adhesion through β1-mediated signaling and actin-myosin contractility, effectively rescuing some of the cellular phenotypes associated with COL4A1/4A2 mutations. Collectively, these results suggest that biomaterials are able to shape the matrix and cellular phenotype of the COL4A2+/G702D mutation in patient-derived cells.

scholarly journals Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6100
Author(s):  
Tiziana Servidei ◽  
Donatella Lucchetti ◽  
Pierluigi Navarra ◽  
Alessandro Sgambato ◽  
Riccardo Riccardi ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Biological Processes ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
Pediatric Malignancy ◽  
Patient Heterogeneity ◽  
Microenvironmental Factors ◽  
Potential Impact ◽  
Cellular Phenotypes ◽  
Embryonic Brain Development

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

scholarly journals Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Walaa Hamed Shaker Nasry ◽  
Chelsea K. Martin
Keyword(s):  
Squamous Cell Carcinoma ◽  
Arachidonic Acid ◽  
Oral Squamous Cell Carcinoma ◽  
Prostaglandin E2 ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Tumour Progression ◽  
Low Oxygen ◽  
Acid Pathway ◽  
Arachidonic Acid Pathway

The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.

scholarly journals IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer

Gut ◽  
2016 ◽  
Vol 67 (2) ◽  
pp. 320-332 ◽  
Author(s):  
Thomas A Mace ◽  
Reena Shakya ◽  
Jason R Pitarresi ◽  
Benjamin Swanson ◽  
Christopher W McQuinn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Checkpoint Inhibitors ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Smooth Muscle Actin ◽  
Immunohistochemical Analysis ◽  
Genetically Engineered ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma

ObjectiveLimited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy.DesignTranscription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL−G12D, Trp53LSL−R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.ResultsPSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L−CD44−). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012).ConclusionsThese preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

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