Flies to Humans-Humans to Flies: A Virtuous Circle of Colorectal Cancer Prevention

The two Nobel prizes in physiology or medicine of 1995 and 2011 establish Drosophila genetics as a signifi cant contributor of genes and signaling pathways relevant to human disease, including innate immunity and cancer. Other than providing clues on mammalian gene homologue function, relatively little attention has been paid on the translational aspect of Drosophila genes, microbes and environmental factors that infl uence homeostasis and disease. This is particularly important for colorectal cancer (CRC) prevention, for which molecular diagnostic tools are non-existent. While clinical studies provide a wealth of information on genes and microbes linked to infl ammatory bowel disease (IBD) and CRC, it is unknown if they can serve as biomarkers in terms of CRC prevention. We discuss the line of research showing that many biomarkers of intestinal infl ammation and CRC in humans may be modeled and mechanistically tested in fl ies. Vise versa, genes and processes, such as regenerative infl ammation and aging-associated DNA damage, found in fl ies to promote tumorigenesis may be tested as biomarkers of CRC risk in humans. Thus, modeling human intestinal infl ammation and cancer in fl ies can provide a means to assess causality of conserved genes and microbes that can colonize the fl y intestine. Moreover, successful modeling in fl ies enables the “treatability” of the pertinent biomarkers via dietary, probiotic and pharmacological interventions and paves the way for clinical trials of treatments that may alleviate intestinal infl ammation and the risk for CRC. Review Article Flies to Humans Humans to Flies: A Virtuous Circle of Colorectal Cancer Prevention Elena Kamilari, Yiorgos Apidianakis1* and Myrofora Panagi2* Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus Dates: Received: 22 May, 2017; Accepted: 02 June, 2017; Published: 06 June, 2017 *Corresponding authors: 1Yiorgos Apidianakis, 1 Panepistimiou Ave, Department of Biological Sciences, University of Cyprus, 2109, Nicosia, Cyprus, Tel. 35722893767; E-mail: 2Myrofora Panagi, 1 Panepistimiou Ave, Department of Biological Sciences, University of Cyprus, 2109, Nicosia, Cyprus, Tel. 357-22893967; Email:


Introduction
The genetic and histological suitability of fl ies for basic research on CRC During the last two decades Drosophila has become a powerful model for exploring the links between infl ammation and colorectal cancer (CRC). The fully sequenced genome, the high degree of human disease-related gene homology with fl ies (up to 75%), the reduced genetic redundancy, the great availability of genetic tools enabling spatial and temporal manipulation of cells, as well as, the evolutionary conservation of signaling pathways controlling vital biological processes and immunity, make Drosophila a suitable model host for the identifi cation of candidate biomarkers implicated in tumorpromoting infl ammation [1,2]. In addition, the small size, the low cost of maintenance and the easy delivery of orally administrated drugs facilitate whole-animal screening for molecular compounds affecting stem cell mediated carcinogenesis [3,4]. Remarkably, there are at least 60 chemical compounds originally known for their activity in human cells that demonstrably have the same molecular mechanism of action in fl ies [2].
The intestine is the most rapidly self-renewing tissue of the human body. Intestinal epithelium is continuously exposed to pathogens and chemicals of the lumen leading to enterocyte highly endoreplicating enterocytes and the visceral muscle [1].
The fl y intestine generally lacks crypts that support multiple progenitor cells and villi. These appear necessary for maximal nutrient absorption in mammals, but in fl ies a monolayer of epithelial cells surrounded by two layers of visceral muscle suffi ces for homeostasis. In addition to the mucus layer, the Drosophila gut lumen is surrounded by a chitin layer, the peritrophic matrix that confers extra protection against pathogens [10].
Using fl ies for identifying genetic and microbial biomarkers of risk for CRC Fly  the number of human bacteria that can colonize fl ies is far more than those found naturally. They promote growth by modulating nutrient metabolism and absorption [40] and participate in the shaping of gastrointestinal immune landscape [41,42]. Therefore, pinpointing the mechanisms by which gut microbiota affects health and disease, may help to suggest new therapeutic approaches to alleviate microbiotadirected infl ammation and CRC incidence. Bacterial monoassociations or poly-associations with germ-free fl ies would provide insights regarding the contribution of symbiotic bacteria at the species level in intestinal disease.

Mammalian genetic and microbial biomarkers of risk for CRC
Most CRC cases are sporadic, that is, with no known genetic component attributed to them (70%-80% of all cases) and usually appear at an old age [43,44]. Hereditary forms of CRC include familial adenomatous polyposis (~1%), non-polyposis hereditary CRC or Lynch syndrome (2%-5%) and MYH-gene associated polyposis (<1%) [45]. Interestingly, molecular and cellular alterations precede morphological changes of the intestinal mucosa, and may predispose for tumorigenesis [46,47]. This must be true also for intestinal microbes and their balance [48]. Such alterations may be blamed for the recurrence of adenomatous polyps after surgical excision [49]. Therefore, ongoing efforts turn towards fi nding specifi c genetic and microbial markers that will allow the early detection of CRC appearance in terms of personalized medicine and treatment.
A hallmark of transition from normal colonic epithelium to neoplastic is genomic instability (GI), which is divided to chromosomal instability (CIN), microsatellite instability (MSI) and epigenetic instability (EI) [44]. The most familiar form of GI is CIN, which is implicated in 80%-85% of colorectal tumors the serine/threonine kinases, CK1 and GSK3/, phosphorylate -catenin, which is guided by the F box/WD repeat protein -TrCP, for degradation to the proteasome. In the absence of signaling, TCF/LEF is not activated by -catenin and its targets are suppressed by Groucho [58]. The TCF binding sites are also similar between vertebrates and Drosophila [59]. The function of -catenin as a TCF activator is strictly regulated by the multiprotein complex that involves APC, which when mutated -catenin is activated to induce tumor-promoting genes, such as Myc [60].

Translational studies for identifying "treatable" biomarkers of risk for CRC using Drosophila
Dietary L-glutamate also stimulates intestinal cell proliferation and growth via regulation of Ca2+ signaling [135]. This plasticity of ISC to nutrient availability could be used to target