The dark side of fly TNF

Abstract

The fruit fly Drosophila is an important model for biological research; however, due to its relatively short lifespan its relevance in cancer research is often questioned.  Nevertheless, among many other intriguing Drosophila models, scribble group mutants provided early evidence for the existence of tumour suppressor genes and their importance in mammalian systems is beginning to emerge. In this review, I discuss recent advances in our understanding of the phenotypes of scrib group gene mutants, in which the activation of JNK signaling plays a crucial role. Several mechanisms can account for the activation of JNK within scrib group mutant cells, including a mechanical stress triggered by the loss of polarity, cell competition, intrinsic tumour suppression by autonomous production of Eiger, and an inflammatory response mediated by Eiger-producing haemocytes. Eiger, the sole Drosophila homolog of tumour necrosis factor, is emerging as a 'danger signal' initiated upon the presence of external pathogens, damaged tissues, and the appearance of pre-malignant cells. Remarkably, in the presence of the Ras oncoprotein Eiger can act as a tumor promoter by stimulating invasive migration and delaying the onset of metamorphosis.

Acknowledgements

Funding was provided by Cancer Research UK. I thank Rhoda Stefanatos for comments on the manuscript. I apologize to colleagues whose work could not be cited due to space restrictions.

Figures and Tables

Figure 1 All roads lead to JNK. Diagram with the proposed mechanisms for the activation of JNK after the loss of scrib group genes. JNK pathway activation normally results in the death of the mutant cells; however, in the presence of oncogenic Ras JNK can promote tumor progression. See the text for details.

Figure 2 Eiger/dTNF is primarily expressed by tumor-associated hemocytes. The confocal image displays a Ras^V12/scrib imaginal disc tumor. The tumor cells are labelled with GFP (green), Eiger immunostaining is in red and nuclei are shown in blue. The Eiger staining is shown in grey in the lower part. The white arrow points to a tumor-associated cell that expresses high levels of Eiger. These tumor-associated cells were identified as plasmatocytes, a sub-type of haemocytes.23 The red arrow points to a tumor cell displaying Eiger staining in the form of intracellular puncta, identified previously as endocytic compartments.22