Cancers cells also exhibit a metabolic switch where they reprogram their metabolism to use an alternative and less abundant anabolic pathway to sustain their growth. (2018). J. Dev. Alterations in the composition of the core proteins (HPO, WTS, SAV, MATS) of the pathway trigger Yki translocation into the nucleus that binds tissue-specific partners and induces the expression of its target genes, among them: CyclinE, dIAP1 and MYC (Harvey et al., 2003; Pantalacci et al., 2003; Neto-Silva et al., 2010; Ziosi et al., 2010). (2010). doi: 10.1038/nature10144, Caussinus, E., and Gonzalez, C. (2005). Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. 451, 548–555. Nat. La consanguinidad, según el Diccionario Terminológico de Ciencias Medicas, se define como «el parentesco natural de individuos que descienden del mismo tronco». Drosophila melanogaster strains. Today 11, 119–126. Planteamiento de situaciones y sus soluciones. Drosophila is also offering a significant contribution to the investigation of organotypic cancers, since despite the evident differences at the macroscopic level, organ cells and functional units are usually well conserved at the biochemical and structural levels respectively. This pathway is part of the MAP kinase signaling that, in addition to ERK1/2, also includes JNK1/2/3, p38/MAPK, and ERK5, which mainly respond to stress activators (Morrison, 2012). (2003). Microbiol. Feedback amplification loop drives malignant growth in epithelial tissues. Use the link below to share a full-text version of this article with your friends and colleagues. doi: 10.1371/journal.pmed.1001200, Carmeliet, P., and Jain, R. K. (2011). 282, 1368–1382. Cancer 13, 246–257. Rev. doi: 10.3171/2014.7.JNS131644, Ruivo, C. F., Adem, B., Silva, M., and Melo, S. A. 4, 21–30. Interestingly, we observed that Myc in Drosophila induced autophagy in the fat body and this was enough to enhance survival of the whole animals upon starvation (Parisi et al., 2013). Las hembras F1 son todas normales mientras que los machos son hemofílicos y raquíticos. A new Drosophila APC homologue associated with adhesive zones of epithelial cells. EMBO J. doi: 10.1101/cshperspect.a008904, Edwards, A., Gladstone, M., Yoon, P., Raben, D., Frederick, B., and Su, T. T. (2011). 81, 687–714. Regulation of prostate cancer progression by the tumor microenvironment. •Variación discreta (número de quetas o facetas en Drosophila, vértebras en serpientes, bandas en caracoles, plumas en aves, escamas en peces...) •Para describir su variación se utilizan métodos estadísticos tales com la media y la varianza •Son caracteres de gran importancia •Agrícola y ganadera •Médica y … (1997). On the contrary, adenocarcinoma of the prostate is an aggressive tumor that rapidly progresses to a metastatic stage that can be partially blocked by androgen therapy (Shiao et al., 2016). doi: 10.1038/nrg751, Stoiber, K., Naglo, O., Pernpeintner, C., Zhang, S., Koeberle, A., Ulrich, M., et al. Biol. Science 302, 1227–1231. 18, 758–770. doi: 10.1038/ng1632, Chen, G., Kong, J., Tucker-Burden, C., Anand, M., Rong, Y., Rahman, F., et al. doi: 10.1038/ncb1051, Parisi, F., Riccardo, S., Daniel, M., Saqcena, M., Kundu, N., Pession, A., et al. Rev. Recent Results Cancer Res. 29, 3424–3434. Genetic studies of assortative mating—a simulation study. Natl. 207, 73–91. Cell 117, 107–116. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. En base a estos descubrimientos y a los estudios realizados en 1906 por el zoologo estadounidense Thomas H. Morgan sobre los cromosomas de la mosca del vinagre (Drosophila melanogaster), se pudo elaborar la teoria cromos6mica de la herencia donde se establecia de manera inequívoca la localizac16n fisica de los genes en la celula. 7, 295–302. CSCs can arise from normal stem cells whose long lifespan favors the accumulation of genetic mutations responsible for the malignant phenotype. (2011). The Salvador-Warts-Hippo (SWH) tumor suppressor pathway was discovered first in Drosophila as a regulator of organ size (Pan, 2010; Yu et al., 2015) and later in humans, where it was found to be fundamental in the regulation of cancer growth (Harvey et al., 2013). Gen-gen tersebut diaktifkan secara berurutan. doi: 10.1038/nrd4281, Saxton, R. A., and Sabatini, D. M. (2017). MYC is one of the most studied oncogenes, and its misexpression is associated with various tumor types including meningioma, Burkitt's lymphoma, medulloblastoma and hepatocellular carcinoma (Hsieh and Dang, 2016). (2011). Regarding cancer, JAK- STAT, APC, Wnt, Notch and other signaling molecules, deeply characterized in Drosophila and shared with humans, are precious for cancer drug development. Cells 7:E121. PIP3 recruits several Ser/Thr kinases to the plasma membrane, including Akt/PKB and PDK1 (3′-phosphoinosite-dependent protein kinase-1), while its activation results in the inhibition of Glycogen Synthase Kinase-beta (GSK3-β), a conserved kinase that not only controls energy metabolism by inactivation of Glycogen Synthase, but also regulates Wnt signaling by controlling β-catenin/armadillo (Xu et al., 2009) and Myc stability (Bellosta and Gallant, 2010). Semin. Cell Rep. 14, 1477–1487. 2. Alteration of cell polarity with the downregulation of the SWH (Salvador-Hippo-Warts) pathway, together with RasV12, triggers downstream events, including activation of the MAPK signaling that stabilize Myc protein (Galletti et al., 2009) resulting in robust cellular growth. 1988. Genes Evol. 116, 181–199. DROSOPHILA MELANOGASTER Pregunta Problema ¿Qué características ambientales afectan el ciclo de vida y reproducción de la Drosophila Melanogaster silvestre? Cell Biol. Cell Biol. doi: 10.1016/j.stem.2014.02.006, Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., et al. Linking colorectal cancer to Wnt signaling. Cell 18, 288–299. doi: 10.3390/molecules18021704, Keywords: Drosophila cancer modeling, cancer biology, oncogene, tumor suppressor, tissue growth, signaling, metabolism, therapeutic approaches, Citation: Mirzoyan Z, Sollazzo M, Allocca M, Valenza AM, Grifoni D and Bellosta P (2019) Drosophila melanogaster: A Model Organism to Study Cancer. Assortative Paarung und Selektionserfolg bei Drosophila melanogaster. Diversas técnicas de análisis estadístico para la detección de genes neutrales y/o adaptativos. Nat. Une situation analogue pourrait se produire dans quelques populations d'animaux domestiques, qui sont divisées en étages avec des niveaux génétiques diférents, les accouplements se produisant surtout entre animaux du měme étage. (2016). The hippo signaling pathway in development and cancer. análisis morfométricos de los genitales externos e internos de dos poblaciones de Drosophila mercatorum y sus híbridos colectadas en el Desierto de la Tatacoa (Huíla) y el Valle del Patía ... Finalmente la Selección sexual, propone que son ... rísticas externas y posterior al cruce … Tumor cells escape the anti-proliferative effect of tumor suppressor genes, such as RB (retinoblastoma-associated) and TP53 genes (Duronio and Xiong, 2013), through mutations in these genes, which result in uncontrolled growth (Hanahan and Weinberg, 2000, 2011; Hariharan and Bilder, 2006). Drosophila brat and human ortholog TRIM3 maintain stem cell equilibrium and suppress brain tumorigenesis by attenuating notch nuclear transport. Therefore, Myc is strictly controlled both transcriptionally and post-translationally, where its protein stability is controlled by phosphorylation events downstream of RAS/ERK and GSK3β kinases with a signaling conserved in flies and mammals (Galletti et al., 2009; Parisi et al., 2011). It is a process by which small molecules are screened for their effect on the phenotype in cells, tissue or whole animals, where a more physiological environment better describes the pharmacokinetics and toxicological effects of a drug. Cell Metab. Alterations in these proteins provoke continued cell proliferation, loss of differentiation and complete loss of tissue architecture, resulting in neoplastic overgrowth (Bilder, 2004; Grzeschik et al., 2010; Johnson and Halder, 2014). The signaling core is characterized by Hemipterus/Hep (JNKK) (Glise et al., 1995), Basket/Bsk (JNK) (Stronach, 2005) and the AP-1 complex, that functions as negative feedback by up-regulating the expression of the Puckered phosphatase (Martin-Blanco et al., 1998). doi: 10.1146/annurev-biochem-061009-102430, Wang, C., Zhao, R., Huang, P., Yang, F., Quan, Z., Xu, N., et al. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. The diverse roles of the TNF axis in cancer progression and metastasis. J. Med. 1, 144–154; discussion 153. doi: 10.1242/dmm.000950, Pavlova, N. N., and Thompson, C. B. Drosophila melanogaster en la nomenclatura científica, és una eina útil per adreçar pràc-ticament qualsevol recerca de tipus bio-mèdic. 3, 176–188. This low level of inflammation increases the levels of ROS and induces DNA and protein damage that may increase the risk of cancer (Lafontan, 2014; Mraz and Haluzik, 2014). (2012). Rep. 3:srep02120. In the second part, we analyze few physiological mechanisms that uncover potential non-autonomous mechanisms controlling growth, including the relation between the immune cells (macrophages) and the growth of epithelial cells, or the function of lipid metabolism in cancer growth. A. Acad. Densidad de población y selección artificial para producción de biomasa en "Drosophila malanogaster" By Ana María Pérez López Topics: Drosophila melanogaster -- Xenética de poboacións -- Teses e escritos académicos, Mellora xenética -- Teses e escritos académicos Its function is variable and depends also on the cellular environment: it can indeed induce cell proliferation and migration, but its major role is to induce apoptosis (Igaki, 2009). Biol. Un estudio experimental con drosophila melanogaster. Sci. (2000). The role of the inflammatory response to combat infection and tissue injury, through the activation of the immune cells, is conserved also in Drosophila's circulating hemocytes (Lemaitre and Hoffmann, 2007), where most of the signals activated in the fat body results also in ROS production (Dionne, 2014; Vlisidou and Wood, 2015). MYC and metabolism on the path to cancer. (2013). doi: 10.1002/dvdy.24420, Cancer, C. G. o. E. S. o. O. (2014). doi: 10.1016/j.ejca.2012.02.063, Christofi, T., and Apidianakis, Y. 9, 887–901. The prostate epithelium is characterized by the abundance of exosomes, microvesicles secreted from the endosomal multivesicular body (MVB) that fuse with sperm to modulate its activity and protect its homeostasis (Wilson et al., 2017). Immunol. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. PLoS Genet. 5, 921–927. Finally, we discuss how Drosophila models are used to find novel interesting therapeutic approaches. JCI Insight 2:e87489. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Drug Discov. Lgl, the SWH pathway and tumorigenesis: It's a matter of context & competition! Cell Metab. Interesting studies in flies showed how reduction of the SCF (Skp/Cullin/F-box)-type ubiquitin ligase Ago, homolog of human Fbw7, increased tracheogenesis through up-regulation of the hypoxia-inducible transcription factor Sima/dHIF and of its target, the FGF ligand Bnl (Mortimer and Moberg, 2013). A. PLoS Genet. Cell Biol. Regulation of protein stability by GSK3 mediated phosphorylation. TIPO DE PARTICIPACIÓN: PONENTE. doi: 10.1016/j.ymeth.2014.01.020, Simon-Carrasco, L., Jimenez, G., Barbacid, M., and Drosten, M. (2018). Cell 100, 57–70. 19. doi: 10.3390/ijms19051272, Hirabayashi, S. (2016). J. Hum. In Drosophila's epithelia, the induction of clones bearing lgl, RasV12 mutations identified how tumors are able to recruit vessels to oxygenate the growing mass (Grifoni et al., 2015; Calleja et al., 2016). Another hormone, leptin, a cytokine produced by the adipocytes to control satiety in a signaling circuit of the brain, has also been found up-regulated in tissues from obese people, particularly in women post-menopause, and increased levels of leptin have been associated with higher incidence of breast and other tumors (Ray, 2018). Biol. doi: 10.4161/cc.8.20.9699, Xu, C., Kim, N. G., and Gumbiner, B. M. (2009). doi: 10.1016/S1359-6446(05)03693-7, Wilson, C., Leiblich, A., Goberdhan, D. C., and Hamdy, F. (2017). Nat. Nat. Most of the signaling pathways controlling cell growth and invasion in mammals have a conserved function in flies allowing their modulation into models that mimic tumor's biology in a simple model organism like Drosophila (Millburn et al., 2016). 3. An innate immune response of blood cells to tumors and tissue damage in Drosophila. For this reason, we anticipate that the use of the fruit fly will move fast into the field of precision medicine, contributing to seminal findings in this new era of cancer research. (2018). 207, 542–550. Thus, some degree of assortative mating could already being contributing to selection response in those populations, and the use of additional deliberate assortative mating in animal breeding plans may be of limited interest. doi: 10.1016/j.ceb.2018.02.003, El-Habr, E. A., Levidou, G., Trigka, E. A., Sakalidou, J., Piperi, C., Chatziandreou, I., et al. doi: 10.1053/j.gastro.2009.05.053, Mukherjee, S., Tucker-Burden, C., Zhang, C., Moberg, K., Read, R., Hadjipanayis, C., et al. Genomic instability–an evolving hallmark of cancer. 9, 235–244. 277, 28372–28375. Funding was provided from the Cariplo Foundation 2014–0703 and EHDN 689 for PB and AV, AIRC-IG17252 for DG and MS. Dis. The availability of Drosophila models for multiple cancer types makes pharmacological screens possible against several drugs that aim to restrict proliferation and metastasis. Swiss Med. The PI3K/Target of rapamycin (TOR) signaling pathway is a highly conserved key regulator of growth. B., Macagno, J. P., Stefanatos, R. K., Strathdee, K. E., Cagan, R. L., and Vidal, M. (2010). Guia genetica cuantitativa y consanguinidad 1. Med. doi: 10.1038/nature05585, Mantovani, A., Allavena, P., Sica, A., and Balkwill, F. (2008). In Drosophila the sole TNF-α, called Eiger (Egr), binds two receptors called Wengen (Kanda et al., 2002) and Grindelwald (Andersen et al., 2015), the latter shown necessary for the growth of RasV12/scribble−/− tumors (Andersen et al., 2015). Dev. Copyright © 2019 Mirzoyan, Sollazzo, Allocca, Valenza, Grifoni and Bellosta. Gene dosage imbalance contributes to chromosomal instability-induced tumorigenesis. Genet., 01 March 2019 Assortative mating in selected populations. Development 139, 4524–4535. Rev. Cancer 118, 43–51. Opin. Prospective study of body size throughout the life-course and the incidence of endometrial cancer among premenopausal and postmenopausal women. The last stage of tumorigenesis is represented by the invasive and metastatic capabilities of tumor cells to disrupt the apical-basal cell polarity, a process that is associated with the downregulation of cell-cell contact molecules and the release of metalloproteases (MMP1), lytic enzymes that degrade the extracellular matrix (ECM) allowing tumor cells to escape and colonize an environment that suites them and to acquire new oncogenic properties (Massague and Obenauf, 2016; Lambert et al., 2017). (2006). 283, 2767–2778. Emergent evidence suggests also a key role for non-autonomous signals released by the cells composing the niche, particularly from cancer-associated fibroblasts (CAFs), that are essential to support the growth of cancer cells in this “new” metabolic environment (Lambert et al., 2017). The role of lipids in the control of autophagy. Aspectes tan diferents com les malalties neurodegeneratives, el càncer, la drogoaddicció, les malalties metabòliques o fins i tot els estudis sobre el canvi climà- tic són exemples en què Drosophila ha con-tribuït a conèixer-ne les causes. Cell. doi: 10.1371/journal.pgen.1000374, Riboli, E. (2014). Cell Rep. 9, 1798–1811. Biomed Res. Centre de Documentació i Experimentació en Ciències i Tecnologia Drosophila melanogaster 6 PALLÍ, A. doi: 10.1016/j.tem.2012.11.002, Osman, D., Gobert, V., Ponthan, F., Heidenreich, O., Haenlin, M., and Waltzer, L. (2009). doi: 10.1158/0008-5472.CAN-15-2299, Muzzopappa, M., Murcia, L., and Milan, M. (2017). Cell Metab. Model. (2017). (2011). Human cancer cells signal their competitive fitness through MYC activity. Rev. A second transcriptional repressor is Capicua (Cic), an HMG box-containing protein highly conserved in vertebrates (Simon-Carrasco et al., 2018). (2017). (2010). doi: 10.1016/j.cub.2015.12.064, Froldi, F., Ziosi, M., Garoia, F., Pession, A., Grzeschik, N. A., Bellosta, P., et al. Cell competition: mechanisms and physiological roles. Biological mechanisms linking obesity and cancer risk: new perspectives. In humans, two lgl homologs have been discovered, HUGL-1 and HUGL-2, with HUGL-1 rescuing all the defects of the fly lgl mutant (Grifoni et al., 2004). This articulated system is also tightly regulated by other signaling pathways: for example, in the Drosophila imaginal wing disc, Lgl or aPKC deregulation results in JNK activation to promote Yki nuclear translocation via phosphorylation of Ajuba (Jub), an upstream regulator of the cascade that binds to and inhibits Wts kinase activity (Sun and Irvine, 2013). Genomic binding and transcriptional regulation by the Drosophila Myc and Mnt transcription factors. The role of adipose tissue immune cells in obesity and low-grade inflammation. These data connect the function of HUGL-1 in the maintenance of glioma stem cells with the loss of function of the tumor suppressor PTEN (Gont et al., 2013) and together with those in glioma (Read et al., 2009) show a conserved function for PI3K and EGFR overexpression in these tumors recapitulating many features of the neurogenic subtype of human glioblastoma. Se cruzan entre sí los individuos de la F1 y se obtiene la siguiente F2: Fenotipo Machos Hembras Normal 48 485 Multiple strategies of oxygen supply in Drosophila malignancies identify tracheogenesis as a novel cancer hallmark. J. Biol. Proc. Drosophila AP-1: lessons from an invertebrate. 64, 193–196. 95, 727–748. doi: 10.4161/cc.8.24.10111, Yeatman, T. J. EMBO J. doi: 10.4414/smw.2004.09885, Halaoui, R., and McCaffrey, L. (2015). Phenotype screening is an eligible option when the knowledge about the mechanisms underlying a disease process is not well defined. Recently, a new Drosophila lung cancer model was developed exploiting the tubular structure of the tracheal network (Levine and Cagan, 2016), and considered functionally and anatomically comparable to the vertebrate airways (Andrew and Ewald, 2010). doi: 10.1016/j.stem.2010.11.026, Johnson, R., and Halder, G. (2014). Cancer 1870, 123–136. Sci. Biophys. Sci. 369, 20–27. Acad. doi: 10.1016/j.bbrc.2014.08.015, Jiang, H., and Edgar, B. doi: 10.1038/25533, Orian, A., Grewal, S. S., Knoepfler, P. S., Edgar, B. Introduction. 23, R33–R45. The imaginal discs also represent an excellent model to analyze oncogenic cooperation: thanks to the use of the MARCM system (Lee and Luo, 1999), it is feasible to induce simultaneously in single cells mutations in tumor suppressor genes (e.g., mutations in cell polarity genes and Hippo pathway components and interactors) and oncogenic activating mutations, or to overexpress specific genes (e.g., EGFR, Ras, Myc, Yorki), resulting in tissue overgrowth, alteration of the normal tissue architecture, disruption of the basement membrane, and invasive/metastatic behavior (Brumby and Richardson, 2003; Pagliarini and Xu, 2003; Wu et al., 2010).
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