Search

Epstein‐Barr virus (EBV)‐associated nasopharyngeal carcinoma (NPC) cells have high metastatic potential. Recent research has revealed that the interaction of between tumor cells and the surrounding stroma plays an important role in tumor invasion and metastasis. In this study, we showed the prognostic value of expression of SPARC, an extracellular matrix protein with multiple cellular functions, in normal adjacent tissues (NAT) surrounding NPC. In the immunohistochemical analysis of 51 NPC biopsy specimens, SPARC expression levels were significantly elevated in the NAT of EBER (EBV‐encoded small RNA)‐positive NPC compared to that in the NAT of EBER‐negative NPC. Moreover, increased SPARC expression in NAT was associated with a worsening of overall survival. The enrichment analysis of RNA‐seq of publicly available NPC and NAT surrounding NPC data showed that high SPARC expression in NPC was associated with epithelial mesenchymal transition promotion, and there was a dynamic change in the gene expression profile associated with interference of cellular proliferation in NAT, including SPARC expression. Furthermore, EBV‐positive NPC cells induce SPARC expression in normal nasopharyngeal cells via exosomes. Induction of SPARC in cancer‐surrounding NAT cells reduced intercellular adhesion in normal nasopharyngeal structures and promoted cell competition between cancer cells and normal epithelial cells. These results suggest that epithelial cells loosen their own binding with the extracellular matrix as well as stromal cells, facilitating the invasion of tumor cells into the adjacent stroma by activating cell competition. Our findings reveal a new mechanism by which EBV creates a pro‐metastatic microenvironment by upregulating SPARC expression in NPC. [ABSTRACT FROM AUTHOR]

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization of the multicellular system is cell competition, the elimination of viable unfit or deleterious cells via cell–cell interaction. Studies in Drosophila and mammals have identified multiple mechanisms of cell competition caused by different types of mutations or cellular changes. Intriguingly, recent studies have found that different types of "losers" of cell competition commonly show reduced protein synthesis. In Drosophila, the reduction in protein synthesis levels in loser cells is caused by phosphorylation of the translation initiation factor eIF2α via a bZip transcription factor Xrp1. Given that a variety of cellular stresses converge on eIF2α phosphorylation and thus global inhibition of protein synthesis, cell competition may be a machinery that optimizes multicellular fitness by removing stressed cells. In this review, we summarize and discuss emerging signaling mechanisms and critical unsolved questions, as well as the role of protein synthesis in cell competition. [ABSTRACT FROM AUTHOR]

Emerging evidence has pointed to the noxious effects of senescent cells in various tissues, and senescent cells in the epidermis are known to accumulate with age. We hypothesized that there is a mechanism by which senescent cells in the epidermis are preferentially removed and that the function of such removal mechanism declines as age increases. In this study, we investigated whether Notch signalling is involved in such senescent cell removal. We found that Notch1 receptor was expressed more highly in p16INK4a‐positive senescent cells than in surrounding cells in human epidermis both in young and old subjects. On the other hand, the expression of its ligand JAG1 was decreased in the epidermis of aged subjects. When normal epidermal cells and UVB‐irradiated senescent cells were mixed and three‐dimensional reconstructed epidermis was developed in vitro, the senescent cells were preferentially removed from the basal layer and located in the upper layer. We also found that the depletion of senescent cells from the basal layer was suppressed by JAG1 knockdown in normal cells or using a Notch signalling inhibitor. From these results, Notch signalling may be involved in senescent cell removal in the epidermis and the age‐related decrease of JAG1 expression in the basal layer may lead to accumulation of senescent cells owing to reduced activation of Notch signalling. [ABSTRACT FROM AUTHOR]

Tumors are complex cellular and acellular environments within which cancer clones are under continuous selection pressures. Cancer cells are in a permanent mode of interaction and competition with each other as well as with the immediate microenvironment. In the course of these competitive interactions, cells share information regarding their general state of fitness, with less‐fit cells being typically eliminated via apoptosis at the hands of those cells with greater cellular fitness. Competitive interactions involving exchange of cell fitness information have implications for tumor growth, metastasis, and therapy outcomes. Recent research has highlighted sophisticated pathways such as Flower, Hippo, Myc, and p53 signaling, which are employed by cancer cells and the surrounding microenvironment cells to achieve their evolutionary goals by means of cell competition mechanisms. In this review, we discuss these recent findings and explain their importance and role in evolution, growth, and treatment of cancer. We further consider potential physiological conditions, such as hypoxia and chemotherapy, that can function as selective pressures under which cell competition mechanisms may evolve differently or synergistically to confer oncogenic advantages to cancer. [ABSTRACT FROM AUTHOR]

Oncogenic mutations often trigger antitumor cellular response such as induction of apoptosis or cellular senescence. Studies in the last decade have identified the presence of the third guardian against mutation‐induced tumorigenesis, namely "cell competition." Cell competition is a context‐dependent cell elimination whereby cells with higher fitness eliminate neighboring cells with lower fitness by inducing cell death. While oncogene‐induced apoptosis or oncogene‐induced senescence acts as a cell‐autonomous tumor suppressor, cell competition protects the tissue from tumorigenesis via cell‐cell communication. For instance, in Drosophila epithelium, oncogenic cells with cell polarity mutations overproliferate and develop into tumors on their own but are eliminated from the tissue when surrounded by wild‐type cells. Genetic studies in flies have unraveled that such tumor‐suppressive cell competition is regulated by at least three mechanisms: direct cell‐cell interaction between polarity‐deficient cells and wild‐type cells, secreted factors from epithelial cells, and systemic factors from distant organs. Molecular manipulation of tumor‐suppressive cell competition could provide a novel therapeutic strategy against human cancers. [ABSTRACT FROM AUTHOR]

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin‐Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP‐expressing cells was unknown. Here, we used high‐throughput chemical compound screening to identify cyclooxygenase‐2 (COX‐2) as a key molecule triggering cell competition. Our work shows that COX‐2‐mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase‐cyclic AMP‐PKA pathway that, in the presence of active YAP, induces E‐cadherin internalization leading to apical extrusion. Thus, COX‐2‐induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition. [ABSTRACT FROM AUTHOR]

Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T‐ALL). This resembled the onset of T‐ALL in patients treated by gene therapy for X‐linked severe combined immunodeficiency (SCID‐X1). Following treatment, thymus activity was established, with T lymphocyte production, although no bone marrow contribution was detected. However, some patients developed T‐ALL. The favored explanation for malignant transformation was considered to be genotoxicity due to integration of the retroviral vector next to oncogenes, thereby activating them ectopically. Although plausible, we consider an alternative, mutually nonexclusive explanation: that any condition enabling prolonged thymus autonomy will promote leukemogenesis. In support of this view, two independent studies have recently shown that the efficacy of reconstitution of the bone marrow in the context of SCID‐X1 dramatically influences the outcome of treatment, and that lymphoid malignancies emerge following transplantation of a small number of healthy progenitors. Here, we discuss the most recent data in light of our own studies in thymopoiesis and the conditions that trigger malignant transformation of thymocytes in various experimental and clinical settings. T lymphocyte development takes place in the thymus and depends on the constant import of hematopoietic progenitor cells from the bone marrow. If the influx of healthy progenitors is impaired, the thymus is capable of autonomously maintaining T lymphocyte production. However, prolongation of thymus autonomy leads to the development of T cell acute lymphoblastic leukemia (T‐ALL). [ABSTRACT FROM AUTHOR]

Cell competition is a context‐dependent cell elimination through short‐range cell–cell interaction, in which cells with higher fitness eliminate neighboring less‐fit or oncogenic cells within the growing tissue. Cell competition can be triggered by many different factors such as heterozygous mutations in the ribosomal protein genes (which are called "Minute" mutations), elevated Myc, Yorkie/YAP, Wg/Wnt, JAK‐STAT, Ras, or Src activity, and loss of Mahjong/VprBP, endocytic pathway components, or apicobasal cell polarity. Studies on the mechanisms and roles of cell competition have suggested that cell competition can be divided into two types: selection of fitter cells or elimination of oncogenic cells. The former type of cell competition includes Minute or Myc‐induced cell competition that is considered to be dependent on the relative level of protein synthesis. The later type of cell competition includes tumor‐suppressive cell competition triggered by loss of cell polarity genes such as scribble (scrib) or discs large (dlg). Genetic studies in Drosophila during the past decade have provided significant progress in understanding the mechanisms of these phenomena. At the same time, these studies have now raised new questions; how do different mechanisms contribute or cooperate to drive cell competition, do common mechanisms exist in different types of cell competition, and what are the physiological roles of these cell competition phenomena? Cell competition is a context‐dependent cell elimination through short‐range cell–cell interaction, in which cells with higher fitness eliminate neighboring less‐fit or oncogenic cells. In this review, we summarize recent progresses on the mechanisms and roles of cell competition and discuss outstanding questions, newly emerged questions, and future perspectives. [ABSTRACT FROM AUTHOR]

Cells heterozygously mutant for a ribosomal protein gene, called Minute/+ mutants, are eliminated from epithelium by cell competition when surrounded by wild‐type cells. Whereas several factors that regulate Minute cell competition have been identified, the mechanisms how winner/loser status is determined and thereby triggers cell competition are still elusive. To address this, we established two assay systems for Minute cell competition, namely (i) the CORE (competitive elimination of RpS3‐RNAi‐expressing cells) system in which RpS3‐RNAi‐expressing wing pouch cells are eliminated from wild‐type wing disc and (ii) the SURE (supercompetition of RpS3‐expressing clones in RpS3/+ tissue) system in which RpS3‐over‐expressing clones generated in RpS3/+ wing disc outcompete surrounding RpS3/+ cells. An ectopic over‐expression screen using the CORE system identified Wg signaling as a critical regulator of Minute cell competition. Activation of Wg signaling in loser cells suppressed their elimination, whereas down‐regulation of Wg signaling in loser cells enhanced their elimination. Furthermore, using the SURE system, we found that down‐regulation of Wg signaling in winner cells suppressed elimination of neighboring losers. Our observations suggest that cellular Wg signaling activity is crucial for determining winner/loser status and thereby triggering Minute cell competition. [ABSTRACT FROM AUTHOR]

In multicellular organisms, incidentally emerging suboptimal cells are removed to maintain homeostasis of tissues. The unfavorable cells are excluded by a process termed cell competition whereby the resident normal cells actively eliminate the unfit cells of the identical lineage. Although the phenomenon of cell competition was originally discovered in Drosophila, a number of recent studies have provided implications of cell competition in tissue regeneration, development and oncogenesis in mammals. Here the roles of cell competition in fly to mammals are discussed. [ABSTRACT FROM AUTHOR]

Pigment cells in zebrafish − melanophores, iridophores, and xanthophores − originate from neural crest-derived stem cells associated with the dorsal root ganglia of the peripheral nervous system. Clonal analysis indicates that these progenitors remain multipotent and plastic beyond embryogenesis well into metamorphosis, when the adult color pattern develops. Pigment cells share a lineage with neuronal cells of the peripheral nervous system; progenitors propagate along the spinal nerves. The proliferation of pigment cells is regulated by competitive interactions among cells of the same type. An even spacing involves collective migration and contact inhibition of locomotion of the three cell types distributed in superimposed monolayers in the skin. This mode of coloring the skin is probably common to fish, whereas different patterns emerge by species specific cell interactions among the different pigment cell types. These interactions are mediated by channels involved in direct cell contact between the pigment cells, as well as unknown cues provided by the tissue environment. [ABSTRACT FROM AUTHOR]

Chimerism is produced by the somatic fusion of two or more genetically distinct conspecific individuals. In animals, the main cost of fusion is competition between genetically different cell lineages and the probability of original cell line replacement by more competitive invasive lines, which limits its natural frequency (3%-5%). In red and brown seaweeds, chimerism is widespread (27%-53%), seemingly without the negative outcomes described for animals. The rigidity of cell walls in macroalgae prevents cell motility and invasions. In addition, in moving waters, most somatic fusions involve the holdfast. Histological observations in laboratory-built bicolor macroalgal chimeras indicated that upright axes emerge from the base of plants by proliferation and vertical growth of discrete cell groups that include one or just a few of the cell lineages occurring in the holdfasts. Laboratory experiments showed growth competition between cell lineages, thus explaining lineage segregation during growth along originally chimeric erect axes. Genotyping of the axes showed more heterogeneous tissues basally, but apically more homogeneous ones, generating a vertical gradient of allele abundance and diversity. The few chimeric primary branches produced, eventually became homogenous after repeated branching. Therefore, coalescing macroagae exhibit a unique pattern of post-fusion growth, with the capacity to reverse chimerism. This pattern is significantly different from those in animals and land plants, suggesting chimerism is a biologically heterogeneous concept. [ABSTRACT FROM AUTHOR]

Tumor progression is classically viewed as the Darwinian evolution of subclones that sequentially acquire genetic mutations and autonomously overproliferate. However, growing evidence suggests that tumor microenvironment and subclone heterogeneity contribute to non-autonomous tumor progression. Recent Drosophila studies revealed a common mechanism by which clones of genetically altered cells trigger non-autonomous overgrowth. Such "oncogenic niche cells" (ONCs) do not overgrow but instead stimulate neighbor overgrowth and metastasis. Establishment of ONCs depends on competition and cooperation between heterogeneous cell populations. This review characterizes diverse ONCs identified in Drosophila and describes the genetic basis of non-autonomous tumor progression. Similar mechanisms may contribute to mammalian cancer progression and recurrence. [ABSTRACT FROM AUTHOR]

Recent results show that, during the process known as cell competition, winner cells identify and kill viable cells from a growing population without requiring engulfment. The engulfment machinery is mainly required in circulating macrophages (hemocytes) after the discrimination between winners and losers is completed and the losers have been killed and extruded from the epithelium. Those new results leave us with the question as to which molecules allow winner cells to recognize and impose cell death on the loser cells during cell competition. [ABSTRACT FROM AUTHOR]

Eukaryotic pseudouridine synthases direct RNA pseudouridylation and bind H/ACA small nucleolar RNA (snoRNAs), which, in turn, may act as precursors of microRNA-like molecules. In humans, loss of pseudouridine synthase activity causes dyskeratosis congenita (DC), a complex systemic disorder characterized by cancer susceptibility, failures in ribosome biogenesis and telomere stability, and defects in stem cell formation. Considering the significant interest in deciphering the various molecular consequences of pseudouridine synthase failure, we performed a loss of function analysis of minifly ( mfl), the pseudouridine synthase gene of Drosophila, in the wing disc, an advantageous model system for studies of cell growth and differentiation. In this organ, depletion of the mfl-encoded pseudouridine synthase causes a severe reduction in size by decreasing both the number and the size of wing cells. Reduction of cell number was mainly attributable to cell death rather than reduced proliferation, establishing that apoptosis plays a key role in the development of the loss of function mutant phenotype. Depletion of Mfl also causes a proliferative disadvantage in mosaic tissues that leads to the elimination of mutant cells by cell competition. Intriguingly, mfl silencing also triggered unexpected effects on wing patterning and cell differentiation, including deviations from normal lineage boundaries, mingling of cells of different compartments, and defects in the formation of the wing margin that closely mimic the phenotype of reduced Notch activity. These results suggest that a component of the pseudouridine synthase loss of function phenotype is caused by defects in Notch signalling. [ABSTRACT FROM AUTHOR]

The notion of 'morphogens' is an important one in developmental biology. By definition, a morphogen is a molecule that emanates from a specific set of cells that is present in a concentration gradient and that specifies the fate of each cell along this gradient. The strongest candidate morphogens are members of the transforming growth factor-β (TGF-β), Hedgehog (Hh), and Wnt families. While these morphogens have been extensively described as differentiation inducers, some reports also suggest their possible involvement in cell death and cell survival. It is frequently speculated that the cell death induction that is found associated with experimental removal of morphogens is the manifestation of abnormal differentiation signals. However, several recent reports have raised controversy about this death by default, suggesting that cell death regulation is an active process for shaping tissues and organs. In this review, we will present morphogens, with a specific emphasis on Sonic Hedgehog, a mammalian member of the Hh family, not as a positive regulators of cell differentiation but as key regulators of cell survival. © 2005 Wiley Periodicals, Inc. J Neurobiol 64: 357-366, 2005 [ABSTRACT FROM AUTHOR]

Provides highlights from the workshop entitled "Growth Control in Development and Disease," held in August 2003 in Arolla, Switzerland. Systemic control of growth by hormones and growth factors; Regulation of growth by nutrients; Insulin signalling, caloric restriction and aging; Regulation of growth at the tissue level; Growth and cancer.