Tumorigenesis and cell competition in Drosophila in the absence of polyhomeotic function.

Cell competition is a homeostatic process that eliminates by apoptosis unfit or undesirable cells from animal tissues, including tumor cells that appear during the life of the organism. In Drosophila there is evidence that many types of oncogenic cells are eliminated by cell competition. One exception is cells mutant for polyhomeotic (ph), a member of the Polycomb family of genes; most of the isolated mutant ph clones survive and develop tumorous overgrowths in imaginal discs. To characterize the tumorigenic effect of the lack of ph, we first studied the growth of different regions of the wing disc deficient in ph activity and found that the effect is restricted to the proximal appendage. Moreover, we found that ph-deficient tissue is partially refractory to apoptosis. Second, we analyzed the behavior of clones lacking ph function and found that many suffer cell competition but are not completely eliminated. Unexpectedly, we found that nonmutant cells also undergo cell competition when surrounded by ph-deficient cells, indicating that within the same tissue cell competition may operate in opposite directions. We suggest two reasons for the incompleteness of cell competition in ph mutant cells: 1) These cells are partially refractory to apoptosis, and 2) the loss of ph function alters the identity of imaginal cells and subsequently their cell affinities. It compromises the winner/loser interaction, a prerequisite for cell competition.

Cell competition and tumorigenesis in the imaginal discs of Drosophila.

Cancer is a major health issue and the object of investigations in thousands of laboratories all over the world. Most of cancer research is being carried out in in vitro systems or in animal models, generally mice or rats. However, the discovery of the high degree of genetic identity among metazoans has prompted investigation in organisms like Drosophila, on the idea that the genetic basis of cancer in flies and humans may have many aspects in common. Moreover, the sophisticated genetic methodology of Drosophila offers operational advantages and allows experimental approaches inaccessible in other species. Cell competition is a cell-quality control process that aims to identifying and subsequently removing cells within animal tissues that are unfit, abnormal or aberrant, and that may compromise the fitness or the viability of the organism. It was originally described in Drosophila imaginal discs but later work has shown it occurs in mammalian tissues where it fulfils similar roles. One aspect of the surveillance role of cell competition is to eliminate oncogenic cells that may appear during development or the life of an organism. In this review we have focussed on the work on Drosophila imaginal discs relating cell competition and tumorigenic processes. We briefly discuss related work in mammalian tissues.

Pro-apoptotic and pro-proliferation functions of the JNK pathway of Drosophila: roles in cell competition, tumorigenesis and regeneration.

The Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family. It appears to be conserved in all animal species where it regulates important physiological functions involved in apoptosis, cell migration, cell proliferation and regeneration. In this review, we focus on the functions of JNK in Drosophila imaginal discs, where it has been reported that it can induce both cell death and cell proliferation. We discuss this apparent paradox in the light of recent findings and propose that the pro-apoptotic and the pro-proliferative functions are intrinsic properties of JNK activity. Whether one function or another is predominant depends on the cellular context.

Tumorigenic Properties of Drosophila Epithelial Cells Mutant for lethal giant larvae.

BACKGROUND: Mutations in Drosophila tumor suppressor genes (TSGs) lead to the formation of invasive tumors in the brain and imaginal discs. RESULTS: Here we studied the tumorigenic properties of imaginal discs mutant for the TSG gene lethal giant larvae (lgl). lgl mutant cells display the characteristic features of mammalian tumor cells: they can proliferate indefinitely, induce additional tracheogenesis (an insect counterpart of vasculogenesis) and invade neighboring tissues. Lgl mutant tissues exhibit high apoptotic levels, which lead to the activation of the Jun-N-Terminal Kinase (JNK) pathway. We propose that JNK is a key factor in the acquisition of these tumorigenic properties; it promotes cell proliferation and induces high levels of Mmp1 and confers tumor cells capacity to invade wild-type tissue. Noteworthy, lgl RNAi-mediated down-regulation does not produce similar transformations in the central nervous system (CNS), thereby indicating a fundamental difference between the cells of developing imaginal discs and those of differentiated organs. We discuss these results in the light of the "single big-hit origin" of some human pediatric or developmental cancers. CONCLUSIONS: Down-regulation of lgl in imaginal discs is sufficient to enhance tracheogenesis and to promote invasion and colonization of other larval structures including the CNS. Developmental Dynamics 245:834-843, 2016. © 2016 Wiley Periodicals, Inc.

A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway.

Mutant larvae for the Drosophila gene lethal giant larva (lgl) develop neoplastic tumors in imaginal discs. However, lgl mutant clones do not form tumors when surrounded by wild-type tissue, suggesting the existence of a tumor-suppressing mechanism. We have investigated the tumorigenic potential of lgl mutant cells by generating wing compartments that are entirely mutant for lgl and also inducing clones of various genetic combinations of lgl(-) cells. We find that lgl(-) compartments can grow indefinitely but lgl(-) clones are eliminated by cell competition. lgl mutant cells may form tumors if they acquire constitutive activity of the Ras pathway (lgl(-) UAS-ras(V12)), which confers proliferation advantage through inhibition of the Hippo pathway. Yet, the majority of lgl(-) UAS-ras(V12) clones are eliminated in spite of their high proliferation rate. The formation of a tumor requires in addition the formation of a microenvironment that allows mutant cells to evade cell competition.

[Absence of a relationship between surgical volume and mortality in cardiac surgery units in Spain]. / No hay relación entre el volumen quirúrgico y la mortalidad en los servicios de cirugía cardiaca en España.

INTRODUCTION AND OBJECTIVES: The relationship between the annual number of cardiac procedures at a particular center (i.e., volume) and surgical outcome is controversial. Several studies in western countries indicate that there is an inverse relationship between surgical volume and mortality. We studied the number of procedures carried out at several cardiac surgery units in Spain and their relationship to overall and risk-adjusted mortality. METHODS: This prospective observational study carried out in 6054 patients undergoing cardiac surgery at 16 hospitals represents 34% of all cardiac surgery performed in Spain during 2004. Data on risk factors and outcomes for each patient treated at participating institutions were analyzed. Data from each center were checked by an external referee. Surgical risk was evaluated for each patient using the Parsonnet and EuroSCORE methods, with the aim of determining risk-adjusted mortality. RESULTS: Overall mortality was 7.7% (95% confidence interval, 7.0%-8.4%). The risk-adjusted mortality index was calculated to be 0.81 using the Parsonnet method, and 1.12 using EuroSCORE. The Pearson correlation coefficient for the relationship between the number of procedures carried out at a center and mortality was 0.065 for overall mortality, 0.092 for risk-adjusted mortality (Parsonnet method), and 0.111 for risk-adjusted mortality (EuroSCORE method). After discarding data from the two centers with highest and lowest mortality rates, respectively, the correlations were -0.464, -0.420 and -0.267, respectively. CONCLUSIONS: No statistically significant relationship was found between the number of cardiac procedures carried out at a particular center in Spain and inhospital mortality.

Mitochondrial transcription factor B2 is essential for metabolic function in Drosophila melanogaster development.

Characterization of the basal transcription machinery of mitochondrial DNA (mtDNA) is critical to understand mitochondrial pathophysiology. In mammalian in vitro systems, mtDNA transcription requires mtRNA polymerase, transcription factor A (TFAM), and either transcription factor B1 (TFB1M) or B2 (TFB2M). We have silenced the expression of TFB2M by RNA interference in Drosophila melanogaster. RNA interference knockdown of TF2BM causes lethality by arrest of larval development. Molecular analysis demonstrates that TF2BM is essential for mtDNA transcription during Drosophila development and is not redundant with TFB1M. The impairment of mtDNA transcription causes a dramatic decrease in oxidative phosphorylation and mitochondrial ATP synthesis in the long-lived larvae, and a metabolic shift to glycolysis, which partially restores ATP levels and elicits a compensatory response at the nuclear level that increases mitochondrial mass. At the cellular level, the mitochondrial dysfunction induced by TFB2M knockdown causes a severe reduction in cell proliferation without affecting cell growth, and increases the level of apoptosis. In contrast, cell differentiation and morphogenesis are largely unaffected. Our data demonstrate the essential role of TFB2M in mtDNA transcription in a multicellular organism, and reveal the complex cellular, biochemical, and molecular responses induced by impairment of oxidative phosphorylation during Drosophila development.

Fatal anaphylactoid reaction after primary exposure to aprotinin.

Aprotinin is widely used to prevent bleeding, inhibit systemic inflammatory response and reduce blood transfusions after cardiac surgery. Because it is a bovine protein, aprotinin can induce hypersensitivity reactions. We report a case of fatal anaphylactoid reaction to primary aprotinin exposure in a woman who was admitted for mitral valve replacement. The possibility of anaphylactic reaction should be considered whenever aprotinin is used.

The role of buttonhead and Sp1 in the development of the ventral imaginal discs of Drosophila.

The related genes buttonhead (btd) and Drosophila Sp1 (the Drosophila homologue of the human SP1 gene) encode zinc-finger transcription factors known to play a developmental role in the formation of the Drosophila head segments and the mechanosensory larval organs. We report a novel function of btd and Sp1: they induce the formation and are required for the growth of the ventral imaginal discs. They act as activators of the headcase (hdc) and Distal-less (Dll) genes, which allocate the cells of the disc primordia. The requirement for btd and Sp1 persists during the development of ventral discs: inactivation by RNA interference results in a strong reduction of the size of legs and antennae. Ectopic expression of btd in the dorsal imaginal discs (eyes, wings and halteres) results in the formation of the corresponding ventral structures (antennae and legs). However, these structures are not patterned by the morphogenetic signals present in the dorsal discs; the cells expressing btd generate their own signalling system, including the establishment of a sharp boundary of engrailed expression, and the local activation of the wingless and decapentaplegic genes. Thus, the Btd product has the capacity to induce the activity of the entire genetic network necessary for ventral imaginal discs development. We propose that this property is a reflection of the initial function of the btd/Sp1 genes that consists of establishing the fate of the ventral disc primordia and determining their pattern and growth.