An established Drosophila model of cancer development in epithelial tissues makes use of somatic clones induced in developing imaginal discs. Somatic scrib(-) clones induced in developing eye imaginal discs in larvae are observed to have abnormal morphology and show increased proliferation; however, the scrib(-) clones are eliminated by cell competition when surrounded by wild-type cells and very little scrib(-) tissue is eventually observed in the adult eye (see FBhh0000587). In a genetic screen to identify genes that impact the cell-competition-based elimination of potentially tumorous clones, the Drosophila gene chico was identified. In animals heterozygous for chico, scrib(-) clones in the eye disc or in the wing disc evade cell competition and develop into tumors.
Dmel\chico encodes an insulin receptor substrate that is a core component of the Drosophila Insulin-like Receptor Signaling Pathway (see FBgg0000904 and FBgg0000910). Dmel\chico is orthologous to two human genes implicated in the development of insulin resistance and type 2 diabetes, IRS1 and IRS2 (see FBhh0000171). In flies, expression of chico in the insulin-producing cells (IPCs) of the brain was found to be necessary to maintain normal insulin levels. Reduced expression of chico specifically in the IPCs results in hyperinsulinemia and is sufficient to promote tumorous overgrowth of scrib(-) clones.
A diet-induced increase in insulin levels also triggers tumorigenesis in this system. The antidiabetic (antihyperglycemic) drug metformin was tested under the same dietary conditions and was found to suppress scrib(-) tumorigenesis.
[updated Aug. 2020 by FlyBase; FBrf0222196]
Increased cancer mortality associated with diabetes reflects both increased cancer incidence and decreased survival among people with diabetes who develop cancer (Diabetes Spectrum, https://spectrum.diabetesjournals.org/content/27/4/276).
Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer (Giovannucci et al, 2010; pubmed:20587728).
IRS1 and IRS2 encode proteins that are phosphorylated by insulin receptor tyrosine kinase upon receptor stimulation; they may mediate the control of various cellular processes by insulin. [Gene Cards, IRS1, IRS2; 2020.08.23]
Many to one: 3 human gene to 1 Drosophila gene. The human genes are IRS1, IRS2, and IRS4.
Many to one: 3 human gene to 1 Drosophila gene. The human genes are IRS1, IRS2, and IRS4.
Moderate-scoring ortholog of human IRS1 and IRS2; low-scoring ortholog of IRS4 (1 Drosophila to 3 human). Dmel\chico shares 21-23% identity and 34-37% similarity with the human genes.
