Biomedical and Biotechnology Research Journal (BBRJ)

: 2020  |  Volume : 4  |  Issue : 4  |  Page : 269--273

Understanding the genetics of gastric and esophageal cancer using Drosophila melanogaster as a model organism

Preeti Thiyagarajan, Venkatachalam Deepa Parvathi 
 Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India

Correspondence Address:
Dr. Venkatachalam Deepa Parvathi
Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu


Drosophila melanogaster, a vicious model, has helped in significant discoveries about several conserved mechanisms. The insect intestine had remained unexplored until the identification of adult somatic stem cells which triggered the invention of genetic amenability of this insect organ in powerful and artistic ways. A variety of mechanisms within the fruit flies' intestine are conserved in human gastrointestinal systems and will, therefore, become relevant within the context of human pathologies such as gastrointestinal cancers and obesity. In line with current guidelines, maintaining a high degree of suspicion of hereditary etiology (genetic involvement) helps in disease diagnosis. In this review, genetics of two crucial cancers are discussed. Mutation or transcriptional silencing of the cadherin-1 (CDH1) gene and tumor protein p53 gene is related to familial diffuse gastric cancer (GC) and esophageal adenocarcinoma, respectively. Testing for CDH1 mutations in patients with familial clustering of hereditary diffuse GC has proven consistent. Further studies on the expression and also the alteration within the proteins within the E-CDH pathways and Hippo pathway may function as biomarkers for early detection. Dysregulation of various mechanisms ends up in invasion, proliferation, and metastases. The promise of targeted therapy and personalized medicine in improving the clinical outcome is now closer than it has ever been.

How to cite this article:
Thiyagarajan P, Parvathi VD. Understanding the genetics of gastric and esophageal cancer using Drosophila melanogaster as a model organism.Biomed Biotechnol Res J 2020;4:269-273

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Thiyagarajan P, Parvathi VD. Understanding the genetics of gastric and esophageal cancer using Drosophila melanogaster as a model organism. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 Jan 18 ];4:269-273
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Full Text


Cancer cells

Cancer cells are the revolting bodies without self-control, and therefore, the single cells that travel through the systema lymphaticum or into the circulation caused metastasis. The explanation why genetics and cancer are linked is essentially thanks to the crucial involvement of chromosomes for normal growth and development as hypothesized by Boveri. Structural or numerical abnormalities in chromosomes (imbalance) cause the formation of the revolting bodies.[1]

Hereditary diffuse gastric cancer

Gastric cancer (GC) in step with the WHO is a malignant epithelial tumor of the gastric mucosa with glandular differentiation.[2] Hereditary diffuse GC (HDGC) could be a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall without forming a definite mass. HDGC consists of band cells and originates diffusely throughout the gastric submucosa.[3] Multiple cadherin (CDH) genes have been found in both human and fruit fly. CDH1 gene in humans has been implicated in susceptibility to HDGC. The CDH1 gene encodes epithelial CDH and is found on chromosome 16, whereas? SHG (Shotgun) encodes Drosophila CDH; these are tumor suppressor proteins. E-CDH is involved in regulating cell-cell adhesions, mobility, and proliferation of epithelial cells.[4]

Esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) occurs within the glandular cells of the lower portion of esophagus. The latter produces and releases fluids like mucus. Barrett's esophagus could be a metaplastic transformation of the native esophageal squamous epithelium into columnar epithelium in response to reflux that is the precursor lesion for this cancer.[5] Clinical features include weight loss, dysphagia, and metastasis. p53 also referred to as tumor protein p53 (TP53) or tumor protein could be a gene that codes for a protein that regulates the cell cycle (tumor suppressor) and is found on the seventeenth chromosome.

The fly model

The biology of Drosophila provides a sound model for studying the genetic basis of varied rare diseases (cancer). Fruit fly is orthologous(75% of the genes that causes diseases in humans are found in fruit fly).[6] Their genome is incredibly small, short era, and high fecundity. It takes approximately 10 days at 25°C for an embryo to transform a fertile adult fly, and development is external and easy to culture. The fruit fly model opens the door to research the fundamental mechanisms underlying cancer genetics as most of the genes are conserved in them. Mammalian and Drosophila's alimentary canal share many similarities. The foregut, midgut, and hindgut of Drosophila correspond to the esophagus, intestine, and enormous intestine of mammals [Figure 1].{Figure 1}

Fundamentals for the understanding of cancer genetics in Drosophila

Imaginal discs are disc-shaped structures having high rate of proliferation that become the external structures of the pinnacle, thorax, limbs, and genitalia. There are totally 19 discs of which the epidermis of the head, thorax, and limbs within the fly comes from 9 bilateral pairs of discs, and therefore, the genitalia come from a medial disc. Oncogenes are an altered type of a traditional cellular gene called proto-oncogene. It encodes a regulatory protein with dominant transforming properties, that is, a single copy of the altered sequence can transform a cell, and therefore, the normal sequence cannot block its transforming ability. The oncogenes in Drosophila show a recessive mode of inheritance, also called anti-oncogenes or tumor suppressor genes (they will not cause the event of tumors). Hyperplasia could be a condition where there will be an increase within the number of cells which cause gross enlargement of the affected part (structure is maintained). Neoplastic cells are abnormal mass of cells, the expansion of which exceeds and is uncoordinated therewith of normal tissue and moves the identical manner after cessation of that stimuli that evoked the initial response (structure is not maintained).

Incidence rate

India having a low human development index features a high incidence of esophageal cancer (EC) majorly within the northeast region. Approximately over 40,000 EC cases are reported. The info obtained from the atlas of cancer by the National Cancer Registry (2014) both in northeastern and southern states of Indian subcontinent GC and EC is the major problem affecting the population [Figure 2] and [Figure 3].[6],[7]{Figure 2}{Figure 3}

 The Focus of the Review

The mutations of genes akin to rare diseases such as EAC and HDGC result in dysregulation of developmental pathways.

Hereditary diffuse gastric cancer

HDGC is majorly caused due to the mutation in CDH1.The latter encodes E-CDH in humans. The beta-catenin-binding domain of CDH will help in linking E-CDH to the cytoskeleton. The assembly of the CDH–catenin complex directly regulates the actin cytoskeleton organization and supports the formation of molecular bridges between neighboring epithelial cells.[8] Beta-catenin plays an important role within the Wnt (Wingless-related integration site) signaling pathway that is conserved in Drosophila [Figure 4]. Wnt genes encode cysteine-rich glycoproteins that are involved in sort of cellular processes, differentiation, apoptosis, and polarity.[9] These proteins secreted by cells act by binding to the cell surface receptors majorly frizzled receptors, and therefore, the signal transduction takes place between the cells. The N-terminal extracellular cysteine-rich domain of these frizzled receptors (seven transmembrane proteins) has been found as the Wnt-binding domain.[10] Once after binding to the receptors, beta-catenin acts as a transcriptional activator by translocating to the nucleus and thereby altering the expression of the gene. Inhibition of Wnt catenin pathway affects the cell growth causing developmental defects and tumorigenesis.[11],[12],[13] When Wnt is inactivated, the destruction complex (components of destruction complex- casein kinase-1alpha, glycogen synthase kinase-3,adenomatous polyposis coli and axin) will phosphorylate beta-catenin at N terminal residues. Following binding of Wnt to frizzled receptor, the Doppler Velocity Log will get recruited to the membrane where axin and GSK3-beta will bind, thereby causing phosphorylation of lipoprotein receptor-related protein 5 and 6, increased destabilization of the destruction complex, and decreased degradation of beta-catenin.[14] The hypophosphorylated β-catenin then gets accumulated and translocated to the nucleus interacting with the transcription factor-like T-cell factor and lymphoid enhancer-binding factor (TCF/LEF) to activate the transcription of target genes.[15],[16],[17]{Figure 4}

To study the signaling pathway involved in CDH1 mutation, E-cadherin overexpression and loss of E-CDH modeling were done in Drosophila. The overexpression study revealed that the overexpressed E-CDH can suppress Wnt/beta-catenin signaling pathway by sequestering armadillo (Drosophila beta-catenin homolog) at sites of cell-cell contact. Drugs such as porcupine and tankyrase inhibitors (2-phenylquinazoline) destabilize the destruction complex (axin [rate-limiting component of the beta-catenin]). This therapeutic importance can be studied in Drosophila as cancer genes and signaling pathways are conserved in them. Loss of E-CDH revealed that there was accumulation of beta-catenin homolog due to two reasons.

Presence of nonsequestered beta-cateninNonfunctional destruction complex (APC and GSK3-beta).[18],[23]

High levels of beta-catenin in the cytoplasm subsequently translocate into the nucleus binds to members of the transcription factor and activate the expression of Wnt genes contributing to increased cell proliferation and tumor progression.[24]

Esophageal adenocarcinoma

EC is an aggressive malignancy and sometimes immune to therapy.[25] EAC is majorly caused because of mutations within the Tp53 gene (tumor suppressor gene). Tp53 gene encodes p53 that plays an important role in cyclin-dependent kinase inhibition, apoptosis, and senescence. One in all the most functions of p53 is the maintenance of genome integrity. It has been shown that different types of inducing factors such as radiation, chemicals, radiomimetic drugs, and a few pharmacological treatments can induce DNA damage. When the humiliation is not efficiently repaired, chromatin and genetic makeup will be changed again leading to oncogenic transformation. These alterations in DNA sequence or structure activate p53, which successively transactivates different genes involved in cell cycle arrest, DNA damage repair, or apoptosis. Mutation or deletion of Tp53 will cause the persistence of DNA damage and that will lead to abnormal genetic transformation to the next generation leading to neoplastic transformation.[26],[29] Moreover, the other function that p53 exerts within the maintenance of genome integrity is that.

It exerts a 3'–5' exonuclease activity that is important in DNA recombination, in DNA repair and DNA replicationIt prevents chromosome aberrations inhibiting aneuploidy and polyploidy occurrencesIt blocks DNA replication until complete chromosome segregation.[30],[31]

p53 acts as a tumor suppressor and an oncogene by means of epidermal growth factor receptor (EGFR) and yes-associated protein (YAP) transcriptional coactivator on Hippo pathway. Both EGFR and YAP1 play critical roles in cell survival and maintenance of tumors.[32] Previous studies on cell lines have reported that failure of EGFR inhibition is also because of crosstalk with other oncogenic pathways. EGFR overexpression has been reported to be related to the development of complicated diseases and metastasis. YAP1 mediates EGFR overexpression, increases cell proliferation, and gives out therapy resistance. YAP1 is a key downstream regulator of the Hippo signaling pathway which is controlled by upstream kinases and their adaptors which are tumor suppressors such as Mst1/2, Sav1, and Lats1/2.[20]

Induction of YAP1 results in resistance to 5-fluorouracil and docetaxel (cytotoxics).

Knockdown of YAP sensitizes EC cells to those cytotoxics.[27]

Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics.[16]

A paralog of YAP that is TAZ (domain containing transcription regulator protein 1 (WWTR1) induces AREG (Amphiregulin) production and activation of EGFR signaling.[28],[31] An earlier report revealed that the transcriptional target of YAP that is amphiregulin (EGFR ligand – AREG), whose induction is by anterior gradient homolog 2, contributes to YAP-mediated cell proliferation and migration.[17] TEAD-binding site within the EGFR promoter is also important for YAP1's induction of EGFR.[30] Mutation or deletion of this region diminished EGFR transcriptional induction by YAP1. Thus, Hippo signaling influences EGFR signaling by specific mechanisms [Figure 5] such as.{Figure 5}

Upregulation of EGFR expressionUpregulation of EGFR ligand (AREG).

However, inhibition of EGFR alone does not seem sufficient, and it should be that EGFR is activated through other oncogenic signaling and targeting those pathways is also advantageous.[22],[29]

Drosophila p53 (Dmp53) has similar apoptotic functions as its human homolog (p53) and is, therefore, a lovely model system for studying cancer pathways. The central DNA-binding domain of Dmp53 protein shows partial sequence conservation with Hp53.[19] Mutations in Tp53 are studied in Drosophila. Homolog of YAP in Drosophila is yki (yorkie). Yap binds to the p53 promoter, thereby inducing p53 transcription, p21, and Bax and inhibits anti-apoptotic factors.[21] p53 successively can bind to the promoter of YAP and activate YAP transcription during a positive feedback loop. In this way, YAP and p53 sustain one another to induce apoptosis, thus acting as a tumor suppressor. Just in case of cancer, the p53 combines with YAP and forms a fancy complex that binds with a transcription factor that is recruited onto the regulatory regions of certain genes that enhances gene transcriptions and results in increased cell proliferation [Figure 5].


India is facing a significant health-care burden due to the high prevalence of both the discussed cancers (EC and GC) and its related complications such as metastases, pneumonia, weight loss, intrahepatic jaundice by hepatomegaly, and peritoneal and pleural effusion.[26] Genetic factor is a vital mediator of cancer progression.[33],[34],[35] Mutation or deletion in a gene induces changes within the associated mechanisms that make someone susceptible to the disease progression. Earlier studies show that by means of Wnt signaling, β-catenin accumulates in a complex with transcription factor (TCF/LEF) which changes the target gene expression.[19] Another study reports that genetic and biochemical evidence implicates Yki, the Drosophila ortholog of the mammalian coactivator protein YAP, as an instantaneous direct, critical target of Wts/Lats within the Hpo pathway. Dysregulation of Wnt signaling is linked to a range of cancer including EC and GC, with one of the reports proving that aberrant Wnt signaling ends up in granulosa cell tumorigenesis.[13]

In summary, studies prove that in Drosophila the Wnt ligand signals through their frizzled (FZD) receptor that helps in controlling and recruiting β catenin pathway. Along with CDH 1 they play a vital role in promoting the formation of adherens junction. Other results encompassing the Hpo pathway involving p53 gene in EAC are proved efficiently. These studies grab our attention toward the therapeutic target and treatment for HDGC.


As already mentioned due to their short life span they will not develop cancer, but many genes and pathways are conserved in flies, so if there is a luxation of the oncogenes, then that will lead to the development of the well-known hallmarks of cancer: self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and evading apoptosis. Models help in the evolution of critical information in the understanding of information and therapy for GC and EC. However, more detailed understanding about the molecular events is related to GC for the development of new therapeutic targets for EC and GC.

Future perspective

The future studies in beta-catenin destruction complex and p53 in Drosophila melanogaster will help in revealing the signaling pathways involved in HDGC and in EAC, respectively. This understanding of biological processes of correlation between cell signaling pathways and genetics of cancer may help to develop new therapeutic targets for EC and GC.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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