Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes

Abstract

More than 50 genes have been identified in Drosophila by loss-of-function mutations that lead to overgrowth of specific tissues. Loss-of-function mutations in the lethal giant larvae, discs large, or brain tumor genes cause neoplastic overgrowth of larval brains and imaginal discs. In the present study, the growth and metastatic potential of tumors resulting from mutations in these genes were quantified. Overgrown brains and imaginal discs were transplanted into adults and beta-galactosidase accumulation was used as a marker to identify donor cells. Mutations in these three genes generated tumors with similar metastatic patterns. For brain tumors, the metastatic index (a measure we defined as the fraction of hosts that acquired secondary tumors normalized for the amount of primary tumor growth) of each of the three mutants was similar. Analysis of cell proliferation in mutant brains suggests that the tumors arise from a population of several hundred cells which represent only 1-2% of the cells in third instar larval brains. For imaginal disc tumors from lethal giant larvae and brain tumor mutants, it is shown for the first time that they can be metastatic and invasive. Primary imaginal disc tumors from lethal giant larvae and brain tumor mutants formed secondary tumors in 43 and 53% of the hosts, respectively, although the secondary tumors were, in general, smaller than the secondary tumors derived from primary brain tumors.

Insights into neural stem cell biology from flies

“…It was known from earlier studies that mutations in the brat gene cause massive overproliferation in larval brain tissue (Kurzik-Dumke et al 1992;Woodhouse et al 1998;Arama et al 2000). The new findings demonstrate that Brat is also a cargo of Mira and, together with Pros, segregates asymmetrically to GMCs upon neuroblast division.…”

Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

“…Small pieces of mutant brain that are implanted into the abdominal cavity of female adult¯ies grow rapidly and spread throughout the body cavity, invading normal tissues and organs (Gate , 1978b). Clonal analysis suggest that these brain tumors arise from only a few hundred cells in the mutant brains, comprising 1 ± 2% of total brain cells (Woodhouse et al, 1998). Accumulation of type IV collagenase, an enzyme associated with many human tumors, was observed in tumors derived from lgl mutant brains (Woodhouse et al, 1994).…”

“…The transplanted neuroblasts grow rapidly, forming metastases and secondary malignant tumors, and ®nally kill their host. brat imaginal discs, in spite of their normal phenotype, can also form metastases and secondary tumors in vivo (Woodhouse et al, 1998).…”

Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade

“…BRAT, on the other hand, has been the subject of intense study in recent times (Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006) and as the name suggests, gives rise to brain tumours when mutated (Woodhouse et al, 1998;Arama et al, 2000). Tumours arising in brat animals are highly proliferative, invasive, transplantable and lethal to the animal (Woodhouse et al, 1998).…”

“…Tumours arising in brat animals are highly proliferative, invasive, transplantable and lethal to the animal (Woodhouse et al, 1998). Of interest, tumorigenic alleles of brat disrupt the NHL repeat region, implicating it as having a direct role in tumor suppression (Arama et al, 2000;Loop et al, 2004).…”