Cancer cachexia: lessons from Drosophila

Abstract

Cachexia, a wasting syndrome that is often associated with cancer, is one of the primary causes of death in cancer patients. Cancer cachexia occurs largely due to systemic metabolic alterations stimulated by tumors. Despite the prevalence of cachexia, our understanding of how tumors interact with host tissues and how they affect metabolism is limited. Among the challenges of studying tumor-host tissue crosstalk are the complexity of cancer itself and our insufficient knowledge of the factors that tumors release into the blood. Drosophila is emerging as a powerful model in which to identify tumor-derived factors that influence systemic metabolism and tissue wasting. Strikingly, studies that are characterizing factors derived from different fly tumor cachexia models are identifying both common and distinct cachectic molecules, suggesting that cachexia is more than one disease and that fly models can help identify these differences. Here, we review what has been learned from studies of tumor-induced organ wasting in Drosophila and discuss the open questions.

Keywords: Drosophila; Cachectic factors; Cancer cachexia; Organ wasting.

Fig. 1.

Drosophila tumor models associated with cachexia. Schematics show Drosophila tumor models and their cachexia-related phenotypes of adult intestinal yki^act tumor; adult imaginal disc Ras^V12 scrib^−/− tumor; larval imaginal disc Ras^V12 scrib^−/− tumor; larval imaginal disc Ras^V12 Csk^−/− tumor; and larval imaginal disc Ras^V12 dlg^RNAi tumor. Csk, C-terminal Src kinase; dlg, disc-large 1; Ras^V12, a constitutively active form of Ras oncogene at 85D; scrib, scribble; yki, yorkie.

Fig. 2.

Crosstalk between Drosophila tumors and host tissues. A schematic showing Drosophila cachectic factors known to be secreted from adult and larval tumor models (genotypes shown in brackets) that are associated with pathologies in the oenocyte, fat body and muscle. Increased lipid catabolism in oenocytes and the fat body leads to lipid loss, while reduced glycolysis in the fat body and muscle causes hyperglycemia. Elevated proteolysis in the muscle leads to muscle wasting. Dashed lines indicate predicted regulatory interactions. Tumors in Drosophila tissues are shown in green. Bnl, Branchless; Csk, C-terminal Src kinase; dlg, disc-large 1; Egr, Eiger; Gbb, Glass bottom boat; ImpL2, Ecdysone-inducible gene L2; ISC, intestinal stem cell; Mmp1, Matrix metalloproteinase 1; Pvf1, PDGF- and VEGF-related factor 1; Ras^V12, a constitutively active form of Ras oncogene at 85D; scrib, scribble; Upd, Unpaired; Upd3, Unpaired 3; yki, yorkie.

Fig. 3.

Metabolite changes in Drosophila tumor models. Tumor-secreted factors stimulate host organs to release metabolites into the hemolymph. Metabolites that are typically elevated in Drosophila tumor models include trehalose and amino acids. Tumors in Drosophila tissues are shown in green. Dashed lines indicate predicted directions.