Developmental capacities of benign and malignant neoplasms ofDrosophila

Abstract

The developmental properties of three neoplasms found in lethal mutants ofDrosophila melanogaster were studied and compared with the development of the corresponding wild-type organs. Two of these neoplasms are found in the late larval lethal mutant,lethal (2) giant larvae (l(2)gl) and its allele,lethal (2) giant larvae (l(2)gl). The third neoplasm occurs in the hemizygous lethal male embryos of the mutantNotch (Df(1)N).The mutantsl(2)gl andl(2)gl were shown to possess defects involving imaginal primordia of ectodermal origin, such as the imaginal discs of the adult integument and the imaginal optic primordia in the larval brain. They also have enlarged lymph glands and abnormal gonads, salivary and ring glands. Thel(2)gl andl(2)gl mutations transform the imaginal discs into noninvasive, lethal neoplasms and the imaginal optic primordia in the larval brain into an invasive and lethal neuroblastoma. Both neoplasms were serially subcultured in female adult hosts where they grew rapidly and killed their hosts in 7-14 days. The neoplastic development of thel(2)gl imaginal discs and brain proved autonomous at all stages that were investigated from 10 hour old embryos to mature larvae. When exposed to the hormonal conditions of metamorphosis, the neoplastic tissues,in situ as well as those that had been culturedin vivo, ceased to grow but failed to metamorphose into parts of the adult integument or brain. Furthermore, in almost all cases they failed to resume their growth in the adult fly after metamorphosis.Thel(2)gl brain neuroblastoma changed after prolonged subculturein vivo so that although the cells stopped dividing temporarily at the time of metamorphosis of the host, they resumed their growth shortly thereafter and continued to divide throughout adult development and in the emerged adult. Many of thel(2)gl neuroblastoma cells showed abnormal karyotypes, shapes and sizes after prolonged culturein vivo.Thel(2)gl imaginal disc tissue resembles, in both structure and behavior, certain atelotypic tissue sublines which arise from wild-type imaginal discs after prolonged culturein vivo: the ultrastructure of both types of cells are similar and both cease to grow when exposed to hormonal conditions of metamorphosis. Apparently the epigenetic processes which transform wild-type imaginal discs afterin vivo subculture into atelotypic neoplasms have the same phenotypic expression as the genetic processes at work inl(2)gl imaginal discs.An analysis of several other late larval and larval-pupal mutants with defective imaginal discs, such asl(2)gd andl(1)d.lg.-1 revealed that they also had defects in parts of the brain destined to form adult structures. This observation indicates that mutations that affect imaginal discs of the adult integument also affect the imaginal primordia of the adult brain.The neoplasm in the hemizygous male embryo of the embryonic lethalNotch is a teratoma-like growth which is lethal and invasive; when implanted into female adult hosts it gives rise to a mass of tissue which consists of most cell typ...

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

“…Loss of PAR3 will result in inappropriate activity along these pathways, with sometimes deleterious consequences (15). The potential of polarity proteins as tumor suppressors has been recognized since early studies in Drosophila development found that they restrain tissue proliferation (41). Loss of polarity genes in Drosophila can also synergize with oncogenes to generate tumors that invade and metastasize aggressively (10,42,43).…”

Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module

“…Furthermore, in neuroblastomas from dlg or lgl mutants, at least a proportion of the tumour cells acquire an unlimited capacity for self-renewal (reviewed by Gonzalez, 2007). These brain tumours can be continually propagated through successive transplants in adult host flies, raising the possibility that tumour growth is driven by the deregulation of stem cell self-renewal pathways (Gateff and Schneiderman, 1974;Woodhouse et al, 1998;Caussinus and Gonzalez, 2005). Although it is not known if epithelial tumours develop from stem-like cells (in fact, imaginal discs are not known to contain stem cells, even though they are capable of unlimited selfrenewal), work in Drosophila has long implicated a stem cell origin for neuroblastomas (reviewed by Januschke and Gonzalez, 2008).…”

“…The Scribble/Dlg/Lgl polarity module Scribble, Dlg and Lgl were originally identified in the genetically tractable model organism Drosophila, in which homozygous mutants in any of the genes results in the loss of apicobasal cell polarity and neoplastic tissue overgrowth (Gateff and Schneiderman, 1974;Mechler et al, 1985;Woods and Bryant, 1989;. Due to the similarity in their mutant phenotypes and the genetic interactions observed between them, it has been surmised that Scribble, Dlg and Lgl function in a common pathway to regulate the establishment and maintenance of apicobasal polarity in epithelial cells .…”

The timing of Drosophila salivary gland apoptosis displays an l(2)gl-dose response

“…4,5 The p127 protein forms large homomeric complexes 6,7 and is associated with a series of proteins, among which were identified the heavy chain of nonmuscle myosin-II, 6 designated thereafter as myosin-II, and a yet unknown serine-kinase. 8 Activation of this kinase leads to specific phosphorylation of p127 and results in the dissociation of myosin-II from p127 without affecting its homomerisation.…”