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Journal of Mammary Gland Biology and... May 2023The role of fibroblast growth factor receptor 2 (FGFR2), an important mediator of stromal paracrine and autocrine signals, in mammary gland morphogenesis and breast...
The role of fibroblast growth factor receptor 2 (FGFR2), an important mediator of stromal paracrine and autocrine signals, in mammary gland morphogenesis and breast cancer has been extensively studied over the last years. However, the function of FGFR2 signalling in the initiation of mammary epithelial oncogenic transformation remains elusive. Here, FGFR2-dependent behaviour of nontumorigenic model of mammary epithelial cells was studied. In vitro analyses demonstrated that FGFR2 regulates epithelial cell communication with extracellular matrix (ECM) proteins. Silencing of FGFR2 significantly changed the phenotype of cell colonies in three-dimensional cultures, decreased integrins α2, α5 and β1 protein levels and affected integrin-driven processes, such as cell adhesion and migration. More detailed analysis revealed the FGFR2 knock-down-induced proteasomal degradation of integrin β1. Analysis of RNA-seq databases showed significantly decreased FGFR2 and ITGB1 mRNA levels in breast tumour samples, when compared to non-transformed tissues. Additionally, high risk healthy individuals were found to have disrupted correlation profiles of genes associated with FGFR2 and integrin signalling, cell adhesion/migration and ECM remodelling. Taken together, our results strongly suggest that FGFR2 loss with concomitant integrin β1 degradation is responsible for deregulation of epithelial cell-ECM interactions and this process may play an important role in the initiation of mammary gland epithelial tumorigenesis.
Topics: Humans; Receptor, Fibroblast Growth Factor, Type 2; Integrin beta1; Breast; Epithelial Cells; Extracellular Matrix Proteins; Integrins
PubMed: 37191822
DOI: 10.1007/s10911-023-09537-x -
Frontiers in Immunology 2023Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T... (Review)
Review
Alopecia areata (AA) is a non-scarring hair loss disorder caused by autoimmunity. The immune collapse of the hair follicle, where interferon-gamma (IFN-γ) and CD8+ T cells accumulate, is a key factor in AA. However, the exact functional mechanism remains unclear. Therefore, AA treatment has poor efficacy maintenance and high relapse rate after drug withdrawal. Recent studies show that immune-related cells and molecules affect AA. These cells communicate through autocrine and paracrine signals. Various cytokines, chemokines and growth factors mediate this crosstalk. In addition, adipose-derived stem cells (ADSCs), gut microbiota, hair follicle melanocytes, non-coding RNAs and specific regulatory factors have crucial roles in intercellular communication without a clear cause, suggesting potential new targets for AA therapy. This review discusses the latest research on the possible pathogenesis and therapeutic targets of AA.
Topics: Humans; Alopecia Areata; CD8-Positive T-Lymphocytes; Cytokines; Autoimmunity
PubMed: 37153617
DOI: 10.3389/fimmu.2023.1148359 -
Biomedicine & Pharmacotherapy =... Jul 2023Cardiac hypertrophy is characterized by cardiac structural remodeling, fibrosis, microvascular rarefaction, and chronic inflammation. The heart is structurally organized... (Review)
Review
Cardiac hypertrophy is characterized by cardiac structural remodeling, fibrosis, microvascular rarefaction, and chronic inflammation. The heart is structurally organized by different cell types, including cardiomyocytes, fibroblasts, endothelial cells, and immune cells. These cells highly interact with each other by a number of paracrine or autocrine factors. Cell-cell communication is indispensable for cardiac development, but also plays a vital role in regulating cardiac response to damage. Although cardiomyocytes and fibroblasts are deemed as key regulators of hypertrophic stimulation, other cells, including endothelial cells, also exert important effects on cardiac hypertrophy. More particularly, endothelial cells are the most abundant cells in the heart, which make up the basic structure of blood vessels and are widespread around other cells in the heart, implicating the great and inbuilt advantage of intercellular crosstalk. Cardiac microvascular plexuses are essential for transport of liquids, nutrients, molecules and cells within the heart. Meanwhile, endothelial cell-mediated paracrine signals have multiple positive or negative influences on cardiac hypertrophy. However, a comprehensive discussion of these influences and consequences is required. This review aims to summarize the basic function of endothelial cells in angiogenesis, with an emphasis on angiogenic molecules under hypertrophic conditions. The secondary objective of the research is to fully discuss the key molecules involved in the intercellular crosstalk and the endothelial cell-mediated protective or detrimental effects on other cardiac cells. This review provides a more comprehensive understanding of the overall role of endothelial cells in cardiac hypertrophy and guides the therapeutic approaches and drug development of cardiac hypertrophy.
Topics: Humans; Endothelial Cells; Cardiomegaly; Myocytes, Cardiac; Paracrine Communication; Fibroblasts
PubMed: 37121147
DOI: 10.1016/j.biopha.2023.114799 -
Genes Apr 2023Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of...
Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of preimplantation embryos, oviductal factors are thought to be critical to pregnancy success. However, how oviductal factors regulate embryonic development and the underlying mechanism remain unknown. In the present study, focusing on WNT signaling, which has been reported to be essential for developmental reprogramming after fertilization, we analyzed the receptor-ligand repertoire of preimplantation embryonic WNT signaling, and identified that the WNT co-receptor LRP6 is necessary for early cleavage and has a prolonged effect on preimplantation development. LRP6 inhibition significantly impeded zygotic genome activation and disrupted relevant epigenetic reprogramming. Focusing on the potential oviductal WNT ligands, we found WNT2 as the candidate interacting with embryonic LRP6. More importantly, we found that WNT2 supplementation in culture medium significantly promoted zygotic genome activation (ZGA) and improved blastocyst formation and quality following in vitro fertilization (IVF). In addition, WNT2 supplementation significantly improved implantation rate and pregnancy outcomes following embryo transfer. Collectively, our findings not only provide novel insight into how maternal factors regulate preimplantation development through maternal-embryonic communication, but they also propose a promising strategy for improving current IVF systems.
Topics: Pregnancy; Humans; Animals; Female; Ligands; Embryonic Development; Zygote; Embryo Implantation; Oviducts; Mammals; Wnt2 Protein; Low Density Lipoprotein Receptor-Related Protein-6
PubMed: 37107647
DOI: 10.3390/genes14040891 -
Frontiers in Endocrinology 2023Control of tissue metabolism and growth involves interactions between organs, tissues, and cell types, mediated by cytokines or direct communication through cellular... (Review)
Review
Control of tissue metabolism and growth involves interactions between organs, tissues, and cell types, mediated by cytokines or direct communication through cellular exchanges. Indeed, over the past decades, many peptides produced by adipose tissue, skeletal muscle and bone named adipokines, myokines and osteokines respectively, have been identified in mammals playing key roles in organ/tissue development and function. Some of them are released into the circulation acting as classical hormones, but they can also act locally showing autocrine/paracrine effects. In recent years, some of these cytokines have been identified in fish models of biomedical or agronomic interest. In this review, we will present their state of the art focusing on local actions and inter-tissue effects. Adipokines reported in fish adipocytes include adiponectin and leptin among others. We will focus on their structure characteristics, gene expression, receptors, and effects, in the adipose tissue itself, mainly regulating cell differentiation and metabolism, but in muscle and bone as target tissues too. Moreover, lipid metabolites, named lipokines, can also act as signaling molecules regulating metabolic homeostasis. Regarding myokines, the best documented in fish are myostatin and the insulin-like growth factors. This review summarizes their characteristics at a molecular level, and describes both, autocrine effects and interactions with adipose tissue and bone. Nonetheless, our understanding of the functions and mechanisms of action of many of these cytokines is still largely incomplete in fish, especially concerning osteokines (i.e., osteocalcin), whose potential cross talking roles remain to be elucidated. Furthermore, by using selective breeding or genetic tools, the formation of a specific tissue can be altered, highlighting the consequences on other tissues, and allowing the identification of communication signals. The specific effects of identified cytokines validated through models or trials will be described. Moreover, future scientific fronts (i.e., exosomes) and tools (i.e., co-cultures, organoids) for a better understanding of inter-organ crosstalk in fish will also be presented. As a final consideration, further identification of molecules involved in inter-tissue communication will open new avenues of knowledge in the control of fish homeostasis, as well as possible strategies to be applied in aquaculture or biomedicine.
Topics: Animals; Adipose Tissue; Obesity; Cytokines; Adipokines; Muscle, Skeletal; Bone and Bones; Mammals
PubMed: 36998471
DOI: 10.3389/fendo.2023.1155202 -
Molecules (Basel, Switzerland) Feb 2023Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible... (Review)
Review
Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection. This review outlines the sources of ATP released under physiological and pathological stress and its cell-specific mechanism of action. We further highlight a series of cardiovascular cell-to-cell communications of extracellular ATP signalling cascades in cardiac remodelling, which can be seen in hypertension, ischemia/reperfusion injury, fibrosis, hypertrophy, and atrophy. Finally, we summarize current pharmacological intervention using the ATP network as a target for cardiac protection. A better understanding of ATP communication in myocardial remodelling could be worthwhile for future drug development and repurposing and the management of cardiovascular diseases.
Topics: Adenosine Triphosphate; Receptors, Purinergic P2; Signal Transduction; Cell Communication; Myocardium
PubMed: 36903347
DOI: 10.3390/molecules28052102 -
Science (New York, N.Y.) Mar 2023Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways...
Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.
Topics: Astrocytes; Genetic Testing; High-Throughput Screening Assays; Microfluidic Analytical Techniques; Microglia; Amphiregulin; Autocrine Communication; Gene Expression; Humans
PubMed: 36893254
DOI: 10.1126/science.abq4822 -
Frontiers in Oncology 2023Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of... (Review)
Review
Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all cancer incidences. Lung cancer therapy and prognosis largely depend on the disease's degree at the diagnosis time. Cytokines are soluble polypeptides that contribute to cell-to-cell communication, acting paracrine or autocrine on neighboring or distant cells. Cytokines are essential for developing neoplastic growth, but they are also known to operate as biological inducers following cancer therapy. Early indications are that inflammatory cytokines such as IL-6 and IL-8 play a predictive role in lung cancer. Nevertheless, the biological significance of cytokine levels in lung cancer has not yet been investigated. This review aimed to assess the existing literature on serum cytokine levels and additional factors as potential immunotherapeutic targets and lung cancer prognostic indicators. Changes in serum cytokine levels have been identified as immunological biomarkers for lung cancer and predict the effectiveness of targeted immunotherapy.
PubMed: 36874133
DOI: 10.3389/fonc.2023.1064616 -
Free Radical Biology & Medicine Apr 2023Previously, we showed wild-type (WT) and mutant (mt) forms of p53 differentially regulate ROS generation by NADPH oxidase-4 (NOX4). We found that WT-p53 suppresses...
Previously, we showed wild-type (WT) and mutant (mt) forms of p53 differentially regulate ROS generation by NADPH oxidase-4 (NOX4). We found that WT-p53 suppresses TGF-β-induced NOX4, ROS production, and cell migration, whereas tumor-associated mt-p53 proteins enhance NOX4 expression and cell migration by TGF-β/SMAD3-dependent mechanisms. In this study, we investigated the role of mutant p53-induced NOX4 on the cancer cell secretome and the effects NOX4 signaling have on the tumor microenvironment (TME). We found conditioned media collected from H1299 lung epithelial cells stably expressing either mutant p53-R248Q or R273H promotes the migration and invasion of naïve H1299 cells and chemotactic recruitment of THP-1 monocytes. These effects were diminished with conditioned media from cells co-transfected with dominant negative NOX4 (P437H). We utilized immunoblot-based cytokine array analysis to identify factors in mutant p53 H1299 cell conditioned media that promote cell migration and invasion. We found CCL5 was significantly reduced in conditioned media from H1299 cells co-expressing p53-R248Q and dominant negative NOX4. Moreover, neutralization of CCL5 reduced autocrine-mediated H1299 cell mobility. Furthermore, CCL5 and TGF-beta from M2-polarized macrophages have a significant role in crosstalk and H1299 cell migration and invasion. Collectively, our findings provide further insight into NOX4-based communication in the tumor microenvironment and its potential as a therapeutic target affecting metastatic disease progression.
Topics: Cell Line, Tumor; Culture Media, Conditioned; NADPH Oxidase 4; Reactive Oxygen Species; Secretome; Transforming Growth Factor beta; Tumor Suppressor Protein p53; Humans
PubMed: 36804453
DOI: 10.1016/j.freeradbiomed.2023.02.012