Ross Cagan and colleagues have used Drosophila melanogaster to try to better understand the molecular basis for the links between type 2 diabetes and an increased risk of the development of certain types of cancer.

Credit: Lara Crow/NPG

Feeding D. melanogaster with a diet that includes 1 M sucrose (high dietary sucrose (HDS)) induces insulin resistance and hyperglycaemia, as well as fat accumulation: phenotypic effects that are similar to those seen in patients with type 2 diabetes. The authors compared the growth of green fluorescent protein (GFP)-expressing cells in the eye that also expressed an oncogenic version of ras1 (ras1G12V) and a loss-of-function allele of csk that increases the activity of the tyrosine kinase Src (ras1G12V;csk−/− cells), in larvae fed HDS or a control diet containing 0.15 M sucrose. In larvae fed a normal or HDS diet, csk-null clones rarely survived owing to Src-induced apoptosis, and ras1G12V cells formed only a few small clones. Moreover, only a small number of proliferating ras1G12V;csk−/− clones were evident in larvae exposed to a normal diet, probably because oncogenic Ras1 fails to overcome the apoptosis induced by Src activation. However, in larvae fed HDS, ras1G12V;csk−/− cells proliferated substantially, with the majority of larvae dying before pupariation. In addition, these larvae had GFP-positive cells in the haemolymph system (a blood equivalent), and approximately 19% of larvae developed distant metastases: such secondary ras1G12V;csk−/− tumours were rare in larvae fed a normal diet.

The expression of a hypomorphic akt allele in ras1G12V;csk−/− cells or treatment with the PI3K inhibitor wortmanin reduced the growth of these cells in larvae fed HDS and, conversely, expression of a constitutively active insulin receptor (inRCA) induced clonal overgrowth of ras1G12V;csk−/− eye cells in larvae fed a normal diet. These findings indicate that the PI3K pathway is important for HDS-mediated ras1G12V;csk−/− clonal growth.

in larvae fed HDS, ras1G12V;csk−/− cells proliferated substantially

Normal eye tissue in larvae fed an HDS diet is insulin resistant; however, the tumour cells were found to be responsive to insulin and showed increased glucose uptake, which was reduced by the expression of the hypomorphic akt allele. These data indicate that the expression of ras1G12V;csk−/− results in a reversion of insulin resistance and enables the cells to respond to the increased levels of glucose available in larvae fed HDS. The selective growth advantage of these cells seems to be the evasion of apoptosis: levels of cleaved Dronc (the caspase 3 orthologue in D. melanogaster) were substantially reduced in ras1G12V;csk−/− clones in HDS larvae and inhibitor of apoptosis (IAP) levels were also increased in these cells. Cells that aberrantly survive apoptosis in D. melanogaster have previously been shown to express Wingless (Wg; a WNT homologue) and levels of Wg were increased in ras1G12V;csk−/− clones in larvae fed HDS compared with larvae fed a control diet. Moreover, reduction of Wg expression using RNA interference resulted in the suppression of tumour growth. Further experiments indicated that Wg expression is involved in regulating the response to insulin. Indeed, in insulin-resistant tissues, the expression of inR mRNA was reduced, whereas in cells expressing Wg that were exposed to insulin the expression of inR was increased, indicating that Wg might be part of the reason why ras1G12V;csk−/− cells have overcome insulin resistance. Finally, the authors found that the combined suppression of sugar uptake, Ras–Src–Pi3k signalling and Wg signalling using drugs that target these pathways inhibited tumour growth and increased the survival of larvae fed HDS.

These findings offer a potential molecular explanation as to why patients with metabolic disease are at an increased risk of tumour development.