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In spite of some limitations, because of the anatomical differences between flies and humans, the use of Drosophila's cancer models has been fundamental to understand some basic processes that regulate human cancers, such as the competitiveness of cancer stem cells (CSCs), the importance of tumor microenvironment, cancer cachexia, drug resistance and tumor-associated vasculogenesis, which was recently found to be functionally conserved in fly's cancer. Development 138, 10451055. 9, 235244. Nat. Meningiomas: knowledge base, treatment outcomes, and uncertainties. doi: 10.1016/j.ejca.2012.02.063, Christofi, T., and Apidianakis, Y. In Drosophila, three complexes establish and maintain epithelial polarity: the Crumbs/Stardust/PATJ/Bazooka, the Par6/aPKC (atypical protein kinase-C) and the Scrib/Dlg/Lgl (Scribble/Discs large/Lethal giant larvae) complexes, which are respectively placed at the apical, subapical and baso-lateral membrane domains. Lipid desaturation-the next step in targeting lipogenesis in cancer? The genes associated with all 15 DNA motifs, when they occur in the peak, are enriched in specific Gene Ontology categories and show a distinct mRNA expression pattern, suggesting that there is a core promoter code in Drosophila. doi: 10.1101/cshperspect.a008904, Edwards, A., Gladstone, M., Yoon, P., Raben, D., Frederick, B., and Su, T. T. (2011). Cell Rep. 14, 14771487. The adipose tissue produces pro-inflammatory cytokines including IL-6, IL-8, IFN, and TNF- among others (Scheller et al., 2011; Arango Duque and Descoteaux, 2014), and their over-production in fats from obese, activates the infiltration of macrophages into the adipose tissue inducing a low level of chronic inflammation or adipocyte tissue macrophage infiltration called ATM (Lafontan, 2014; Kuroda and Sakaue, 2017). Drosophila Melanogaster Encyclopedia of Food Sciences and Nutrition (Second Edition) Fruit flies and other insect pests are prevalent in the tropics and the subtropics. 25, 34013410. Models that mimic the growth of epithelial cancer cells and their ability to undergo metastasis in Drosophila have been established by inducing the cooperation between oncogenes (RED) like the active form of Ras (RasV12) together with the loss of function of cell polarity genes (GREEN) (Brumby and Richardson, 2003; Pagliarini and Xu, 2003). Wg activity in the enterocytes (ECs) indirectly drives the expansion of the ISCs by upregulating the JAK-STAT ligands Upd2 and Upd3, acting non-autonomously on ISCs proliferation (Tian et al., 2018). A RANO review. The PI3K/Target of rapamycin (TOR) signaling pathway is a highly conserved key regulator of growth. (2015). doi: 10.1242/dev.026955, Jiang, H., Grenley, M. O., Bravo, M. J., Blumhagen, R. Z., and Edgar, B. Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development. Eur J Cancer 48, 21372145. Nature 446, 325328. doi: 10.1016/j.cub.2015.12.043, Sun, G., and Irvine, K. D. (2013). Front. doi: 10.1016/j.semcdb.2015.08.003, Hulf, T., Bellosta, P., Furrer, M., Steiger, D., Svensson, D., Barbour, A., et al. APC loss-induced intestinal tumorigenesis in Drosophila: roles of ras in Wnt signaling activation and tumor progression. Biol. TNF- in tumors has distinct and overlapping functions to promote tumor growth and proliferation and to activate cell death, functions that are mainly mediated by the activation of TNFR1 that is ubiquitously expressed while TNFR2, mainly expressed in immune cells, is less well understood. The fruitfly Drosophila melanogaster provides a rapid, ethical and cost-effective model system of the kidney. B. doi: 10.1016/S0092-8674(00)80679-0, Ray, A. Drosophila and other small model organisms are helpful to quickly analyze the mode of action of several active compounds in vivo, nevertheless mammalian models are indispensable in the successive phase of drug development to define important pharmacokinetic parameters such as absorption, distribution and metabolism. doi: 10.1038/bjc.2017.374, Stronach, B. In D. melanogaster, the process of developing from a fertilized egg to adult ( Figure 1) requires on average only 9-10 days at 25; however, temperature can greatly influence the speed of this process, with flies cultured at 18 requiring 19 days from egg to adult. Biochim. Adipocyte death and chronic inflammation in obesity. (2018). (2018). Development 132, 25212533. Cell death is induced by the expression of the pro-apoptotic genes hid, reaper and grim, whose activity inhibits the pro-survival protein dIAP1 (Weston and Davis, 2007). Graph representing the number of publications in PubMed found with the terms Drosophila cancer model, in the last 48 years. Rev. 4, 496503. 9:e1003314. doi: 10.1038/nature07205, Markstein, M., Dettorre, S., Cho, J., Neumuller, R. A., Craig-Muller, S., and Perrimon, N. (2014). doi: 10.1038/nature17038, Medioni, C., Senatore, S., Salmand, P. A., Lalevee, N., Perrin, L., and Semeriva, M. (2009). Mutations in CIC and FUBP1 contribute to human oligodendroglioma. mTOR signaling in growth, metabolism, and disease. Science 302, 12271231. doi: 10.1038/nature14298, Anderson, A. M., Bailetti, A. The hippo signaling pathway in development and cancer. Sex determining systems of Drosophila control somatic sexual - Springer The fruit fly, Drosophila melanogaster, is used as a model organism to study disciplines ranging from fundamental genetics to the development of tissues and organs. Phillips, H. S., Kharbanda, S., Chen, R., Forrest, W. F., Soriano, R. H., Wu, T. D., et al. doi: 10.1146/annurev-biochem-061009-102430, Wang, C., Zhao, R., Huang, P., Yang, F., Quan, Z., Xu, N., et al. Apparent Genetic Complexity Generated by Developmental Thresholds: The CSCs can arise from normal stem cells whose long lifespan favors the accumulation of genetic mutations responsible for the malignant phenotype. Cell Biol. (1998). Epithelial tissues are characterized by a specific cell architecture composed of junctions and apical and baso-lateral membrane domains that are crucial for the maintenance of cell-physiological functions. Hippo signaling promotes JNK-dependent cell migration. (2018). doi: 10.1146/annurev.genet.39.073003.100738, Harvey, K. F., Pfleger, C. M., and Hariharan, I. K. (2003). This proto-oncogene is amplified or activated in more than 20% of human tumors, and its activity has been demonstrated to play a central role in the formation of colorectal cancer (CRC). Dis. Mech. In conclusion to this fruit fly lab F1 flies had an overall 100% of wild type flies. Aavikko, M., Li, S. P., Saarinen, S., Alhopuro, P., Kaasinen, E., Morgunova, E., et al. Natl. Complex interactions were found between members of the PI3K/AKT/mTOR pathway and MAPK-, JAK/STAT, and Notch-1-mediated pathways that contribute to meningioma progression (El-Habr et al., 2014). Of particular interest is TNF- that plays an important role in controlling apoptosis and the inflammation processes (Ham et al., 2016). (PDF) Drosophila melanogaster (Meigen, 1830): A - ResearchGate Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Since the accessory gland has a similar structure as the prostate epithelium, characterized by the abundance of exosomes, it could be an optimal model to better study exosome biology in tumors of endocrine origins. Sci. doi: 10.1038/nrc3458, Herranz, H., Eichenlaub, T., and Cohen, S. M. (2016). doi: 10.3390/genes8050131, Pan, D. (2010). Top. Dyn. Cancer 25, T91T104. In our model, PI3K activation mimics PTEN loss of function and hampers Lgl localization at the apical membrane by aPKC cortical recruitment (Paglia et al., 2017). In this review we described most relevant approaches in Drosophila, used to explore cancer mechanisms and therapeutics that contribute to our understanding on tumor initiation and progression. doi: 10.1242/dmm.003970, Arango Duque, G., and Descoteaux, A. Drosophila was used to better understand the functions of the centrosome and microtubule-organizing center (MTOC) in the division of stem cells (Tillery et al., 2018). doi: 10.1080/15384101.2018.1450029, Sinenko, S. A., Hung, T., Moroz, T., Tran, Q. M., Sidhu, S., Cheney, M. D., et al. In summary, all these data suggest the existence of conserved mechanisms between the immune and tumor cells in flies that may recapitulate some of the most evolutionary conserved aspects described in cancer cells. doi: 10.1016/j.cell.2006.01.038, Bettegowda, C., Agrawal, N., Jiao, Y., Sausen, M., Wood, L. D., Hruban, R. H., et al. doi: 10.1038/25533, Orian, A., Grewal, S. S., Knoepfler, P. S., Edgar, B. (2018). 277, 2837228375. doi: 10.1534/genetics.111.127910, Brumby, A. M., and Richardson, H. E. (2003). The fruit fly Drosophila melanogaster unfolds the secrets of innate immunity Acta Paediatr. 1:a001388. Biol. Conclusion: Drosophila and human promoters use different DNA sequences to regulate gene expression, supporting the . doi: 10.1242/dev.01837, Kanda, H., Igaki, T., Kanuka, H., Yagi, T., and Miura, M. (2002). JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. 4:a011254. Dev. PLoS Genet. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Dev. Because of these reasons, Morgan carried out his experiment on Drosophila melanogaster. doi: 10.1016/j.cmet.2014.01.012, DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., and Thompson, C. B. doi: 10.1101/gad.1052803, Lee, T., and Luo, L. (1999). Obesity and diabetes: the increased risk of cancer and cancer-related mortality. (2006). Approximately 89% of these acetylation sites are located within Drosophila melanogaster proteins which are conserved with human, based on DIOPT prediction using a score of 3 or more as cutoff (Hu et al. Cell Biol. PLoS Med. Immunol. 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. Proc. doi: 10.1053/j.gastro.2009.05.053, Mukherjee, S., Tucker-Burden, C., Zhang, C., Moberg, K., Read, R., Hadjipanayis, C., et al. 5:491. doi: 10.3389/fimmu.2014.00491, Bangi, E. (2013). 25, 52945304. 229, 2733. doi: 10.1242/dmm.023317, Moreno, E., and Basler, K. (2004). 31, 306310. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. Cell Dev. Drug Discov. PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1. (2017). Natl. Physical and Linkage Maps for Drosophila serrata, a Model Species for Sci. Quant. In the fruit fly, the circulatory system is open, the heart pumps the hemolymph into the body cavities and the exchange of gases takes place directly within the organs (Medioni et al., 2009). Non-autonomous cell proliferation in the mammary gland and cancer. doi: 10.1111/febs.13235, Walther, T. C., and Farese, R. V. Jr. (2012). 77, 64806488. Regulation of cell growth by Notch signaling and its differential requirement in normal vs. tumor-forming stem cells in Drosophila. doi: 10.1016/j.celrep.2015.12.105, Levinson, S., and Cagan, R. L. (2016). Rapidly proliferating cells have a high metabolic rate and suffer from low oxygen conditions (hypoxia). (2009). The diverse roles of the TNF axis in cancer progression and metastasis. doi: 10.1016/j.celrep.2016.08.019, Lu, L., Li, Y., Kim, S. M., Bossuyt, W., Liu, P., Qiu, Q., et al. Several Drosophila models of stem cell tumors are now available, and a drug screening was successfully carried out highlighting several compounds active on the signaling promoting cancer growth (Markstein et al., 2014). Most soft tropical fruits are prone to infestation by fruit flies. Acad. 4:a014274. Clear differentiation of sexes is found with many types of hereditary variations which can be seen with low power microscope. 12:9. doi: 10.1186/1741-7007-12-9, Roberts, D. L., Dive, C., and Renehan, A. G. (2010). Nat. 20(Suppl. Myc cells thus behave as winners and they are able to repopulate the space of the dying loser cells that are killed by unidentified Myc-dependent mechanisms (Johnston, 2014). Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo. Cell 19, 507520. Drosophila melanogaster as a Model System to Study Mitochondrial doi: 10.1093/emboj/cdg548, Bryant, D. M., and Mostov, K. E. (2008). EGFR signaling regulates the proliferation of Drosophila adult midgut progenitors. The prostate is an exocrine gland of the male reproductive system responsible for the maturation and production of the seminal fluid, with its activity depending on androgens mostly produced by the testis. Introduction to Drosophila | IntechOpen doi: 10.1016/j.ddtec.2012.09.004, Das, T. K., and Cagan, R. L. (2018). Energy transfer in parasitic cancer metabolism: mitochondria are the powerhouse and Achilles' heel of tumor cells. Annu. doi: 10.1101/cshperspect.a001388, Prober, D. A., and Edgar, B. 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. 122, 423. A. doi: 10.1016/j.ydbio.2007.08.025, Grzeschik, N. A., Parsons, L. M., and Richardson, H. E. (2010). Curr. Indeed, publications that use flies to model cancer have exponentially increased in the last 10 years, as shown in the graph of Figure 1, suggesting the relevance of this model to cancer research. Oncotarget 4, 12661279. Because of all these functional homologies to human RAS, its activation in Drosophila is considered a good method to establish models that mimic tumor growth. (2010). The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. Cell. Nature 481, 8589. 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). BMC Biol. 7:13615. doi: 10.1038/ncomms13615, Barker, N., Ridgway, R. A., van Es, J. H., van de Wetering, M., Begthel, H., van den Born, M., et al. Mutant-based analyses have been used extensively to understand the genetic basis of different cellular processes, including development, neuronal function and diseases. Myc activity is finely regulated, and while its expression is required at physiological levels during development, an excess of its activity triggers autonomous cell death and unbalanced growth (Grifoni and Bellosta, 2015). 13, 928942. Curr. In this review we first describe the basic biological mechanisms responsible for uncontrolled growth conserved between humans and flies. doi: 10.1111/febs.13681. Med. Sci. Drosophila melanogaster. Therapeutic drug discovery requires chemical screening, a procedure allowing for the identification of potential new drugs. Rev. A Serrate-expressing signaling center controls Drosophila hematopoiesis. Prospective study of body size throughout the life-course and the incidence of endometrial cancer among premenopausal and postmenopausal women. Natl. Rev. doi: 10.1002/embj.201387454, Cordero, J. Drosophila and mammalian stem cells are similar and they are regulated by homologous signals corroborating the use of the fly in this field of tumor biology. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. This leads to RAF activation and to the formation of the complex with the kinase D-Sor also called MAPKK or MEK that, upon phosphorylation of Rolled, the fly homolog of MAPK or ERK kinases, induces the activation of its final targets (Shilo, 2014). Nat. Molecules 18, 17041719. Conclusion: Drosophila melanogaster has been one of the most fruitful models to study innate immunity. 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). Cell 168, 657669. J. Dev. Inhibition of PI3K/Akt activity is currently used as a therapy in GBM (Zhao et al., 2017). 16, 11391146. The addition of numerous molecular tools has allowed the . As members of PI3Ks and TOR signaling are frequently activated in human tumors, they are attractive targets for cancer treatment. (2007). In Vivo Animal Modeling: Drosophila - ScienceDirect We thank all members of Bellosta's and Grifoni's laboratories and Sheri Zola for their comments on the review. B., Ridgway, R. A., Valeri, N., Nixon, C., Frame, M. C., Muller, W. J., et al. (2000). Oncogene 34, 939950. doi: 10.1016/j.canlet.2015.12.022, Shilo, B. Sci. Genes 8:E131. The art and design of genetic screens: Drosophila melanogaster. 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). Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. World J. Clin. (2009). doi: 10.1016/S1359-6446(05)03693-7, Wilson, C., Leiblich, A., Goberdhan, D. C., and Hamdy, F. (2017). doi: 10.1038/nature10144, Caussinus, E., and Gonzalez, C. (2005). Cancer Res. The combined effect of anti-cancer drugs with radiation has been investigated in Drosophila larvae, producing similar findings to those observed in human cancer cells (Edwards et al., 2011). These larval organs are indeed morphologically and biochemically comparable to mammalian epithelia (Wodarz and Nathke, 2007). Results: Natl. Cases 6, 483492. Cell 98, 779790. Natl. Perspect Med. The physiological activation of the Hippo (HPO) kinase, (MST1/2 in human) (Harvey et al., 2003) consists in the phosphorylation of Warts (WTS), (LATS1/2 in human) (Genevet et al., 2010; Yu et al., 2010) and in the activation of the phosphorylated core complex, that includes Salvador (SAV in human) (Tapon et al., 2002) and Mob/MATS, that in turn, phosphorylate Yki (YAP/TAZ in humans) (Oh and Irvine, 2008). The exosomes are particularly relevant in cancer biology for their implication in tumor progression and survival, since they deliver survival factors, metabolites and miRNAs, that help creating a favorable microenvironment for cancer growth; in addition they also favor drug-resistance by activating mechanisms that favor the elimination of toxic chemicals such as chemotherapeutic products (Ruivo et al., 2017; Namee and O'Driscoll, 2018). Genetics 122 881-890. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. completes it's life cycle in about two weeks and produces large number of progenies from single mating. Physiol. Despite the widespread occurrence of these differences in more than one Drosophila species, the actual selective mechanisms controlling the genetic basis of such variation are not fully understood.
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