This report describes cachexia, IGFBP-related, a Drosophila model of wasting syndrome based on the fly gene Dmel\ImpL2. The ImpL2 protein is functionally orthologous to human insulin-like growth-factor-binding proteins (IGFBP); it has been shown to physically interact with Drosophila insulin-like peptides. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for ImpL2.
None of the human IGFBP genes has been introduced into flies.
Using several different cancer models in Drosophila larvae and adults, wasting of adipose, muscle, and gonadal tissues is observed, similar to the symptoms of cachexia observed in advanced cancers in human. The fly gene ImpL2 has been identified as a key mediator of this process; knockdown or reduced expression of ImpL2 ameliorates wasting phenotypes. The Drosophila gene Pvf1 may act in concert with ImpL2 in some tissues (observed in gut tumor system to impact muscle wasting). The upstream roles of Pten and Pink1 in ImpL2-mediated wasting phenotypes have been investigated.
Animals homozygous for amorphic mutations of ImpL2 have a large body size, primarily due to an increase in the number of cells; in other aspects they are normal in appearance and are fertile. When tested in the larval stage, homozygous animals are severely compromised under starvation conditions. Genetic and physical interactions of Dmel\ImpL2 have been described; see below and in the ImpL2 gene report.
For an additional model of cachexia in flies, see the human disease model report 'cachexia, yki-induced ISC tumor model' (FBhh0001115). One of the conclusions of these studies is that Pvf1 and ImpL2 are independent regulators of the non-autonomous tissue wasting observed with yki-induced ISC tumors.
The Warburg effect (preferential use of aerobic glycolysis by cancer cells) may be one of the contributing factors in the development of cachexia. See human disease model reports 'cancer, aerobic glycolysis (Warburg effect), larval growth ' (FBhh0000502) and 'cancer, epithelial, glycolytic tumor model' (FBhh0000959).
[updated Apr. 2021 by FlyBase; FBrf0222196]
Cachexia is characterized by a dramatic loss of skeletal muscle mass and adipose tissue, resulting in substantial weight loss. It is also known as "wasting syndrome", causing disproportionate muscle wasting, weakness, fatigue, and loss of appetite in affected individuals. Cachexia occurs in many cancers, usually at the advanced stages of disease. [http://www.news-medical.net/health/Cachexia-Wasting-Syndrome-.aspx and https://www.cancer.gov/about-cancer/treatment/research/cachexia]
There are 6 genes that encode insulin-like growth-factor-binding proteins (IGFBP) in human. IGFBP's have a high affinity for insulin-like growth factor, and bind non-IGF ligands, as well. Beyond their endocrine role in IGF transport, IGFBPs function in the pericellular and intracellular compartments, impacting transcriptional regulation, induction of apoptosis and DNA damage repair. (Baxter, 2014; pubmed:24722429).
ImpL2 is functionally orthologous to the insulin-like growth-factor-binding proteins (IGFBP) of human.
