This Drosophila model of epithelial cancer builds upon a model using the fly polarity gene scrib and the fly tumor necrosis factor (TNF) family gene egr (see FBhh0000926), with the addition of an activated form of the Drosophila Ras85D gene. Among the questions addressed is one raised by the dual role of TNF in human cancers, where there is evidence of both pro-tumor and anti-tumor activities.
Tumor necrosis factor (TNF) proteins are transmembrane proteins that can be released from the cell membrane by extracellular proteolytic cleavage; they can act via both autocrine and paracrine signaling. This is a large gene family in human; in Drosophila there is a single TNF gene, eiger (egr). Animals homozygous for the loss-of-function mutation of egr1 are viable and fertile, with minor feeding and immune response phenotypes. Using the scrib model, egr has been found to play a significant role in tumorigenesis in that system. In contrast to the result in wild-type egr animals, somatic scrib(-) clones induced in eye or wing imaginal discs of egr1 homozygous larvae grow aggressively and develop into non-invasive tumors; the animals typically die in the pupal stage. Thus presence of wild-type egr is these experiments serves an anti-tumor function. (See the human disease model report 'cancer, epithelial, TNF-SCRIB-related' FBhh0000926.)
When somatic clones that carry both a scrib(-) mutation and the Ras85DV12 activated mutation are induced in wild-type larvae, invasive tumors are observed (see the human disease model report 'cancer, epithelial, RAS-SCRIB-related' FBhh0000585). However, when the same experiment is done in larvae homozygous for a loss-of-function mutation of egr, the response is less severe and non-invasive, resulting in a hyperplastic rather than a neoplastic pattern of proliferation. In this system, the presence of wild-type egr serves a pro-tumor function; it appears to be required for progression to neoplastic growth. In contrast to the scrib(-) egr(-) result, which appears to disrupt a cell autonomous process, egr in this case appears to act in a non-cell-autonomous fashion. It is postulated that egr expression in tumor-associated hemocytes plays a role in the observed pro-tumor response.
Comparable experiments using animals with RNAi-mediated knockdown of the Drosophila TNF receptor gene grnd give similar results: the extreme invasive phenotypes of scrib(-), Ras85DV12 clones are not observed in animals with reduced levels of grnd.
Based on transplantation experiments in which a small piece of the tumor is implanted in the abdomen of an female adult host and assessed for capacity to regenerate a solid tumor, it has been suggested that the role of egr in tumorigenesis is of a paracrine type, mainly restricted to mediating interactions between tumor-initiating and surrounding wild-type epithelial cells. However, see the human disease model report 'cancer, epithelial, ALG3-related' (FBhh0000929), for which there is support for an endocrine-type function of egr in the context of a cancer disease model.
See also the human disease model reports 'cancer, epithelial, SCRIB-related' FBhh0000587; 'cancer, multiple, RAS-related' FBhh0000474.
[updated Nov. 2018 by FlyBase; FBrf0222196]
TNF-α acts in both transmembrane and soluble forms; the transmembrane form of the ligand appears to mediate therapeutic effects, whereas the soluble ligand is linked to pathologic effects. (Aggarwal et al., 2012; pubmed:22053109).
The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways (Gene Cards, SCRIB; 2017.08.01).
The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular proteolytic cleavage. TNF proteins are expressed predominantly by immune cells and regulate diverse cell functions, including regulation of immune response and inflammation, but also proliferation, differentiation, apoptosis and embryogenesis. The superfamily contains 19 members that bind to 29 members of TNF receptor superfamily. [https://en.wikipedia.org/wiki/Tumor_necrosis_factor_superfamily] This protein family is also called the TNF ligand family.
TNF proteins can act via both autocrine and paracrine signaling (Caldwell et al., 2014; pubmed:25274725).
HGNC currently lists 18 genes in the Tumor Necrosis Factor Superfamily (https://www.genenames.org/data/genegroup/#!/group/781)
Sole TNF family gene in Drosophila (1 Drosophila to many human); Dmel\egr is most closely related to human EDA, TNFSF13, and TNFSF13B.
Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.
None of the TNF receptor genes in human has been identified as orthologous to grnd.
