February 01, 1999
Studies of Fly Tumor May Expand Understanding of Human Cancer
Howard Hughes Medical Institute (HHMI) researchers at Yale
University have "rescued" fruit flies from cancerous tumors by
inserting a cancer-suppressing human gene into the insects. The
scientists believe that their achievement represents the first direct
link between human tumor suppressor genes and those found in the fruit
fly Drosophila.
More broadly, the experiments demonstrate that even though flies and
humans are separated by 800 million years of evolution, the insects can
provide important new insights into human cancers, says HHMI
investigator Tian Xu
at Yale University School of Medicine.
“This finding is important because it is the first example showing that an invertebrate tumor suppressor is also a tumor suppressor in mammals.”
Tian Xu
Tumor suppressor genes produce proteins that normally stop cell
proliferation. When such genes malfunction, they produce defective
proteins that permit cells to proliferate endlessly, producing
tumors.
In a paper published in the February 1999 issue of the journal
Nature Genetics, the researchers showed that inserting the human
"large tumor suppressor" (LATS1) gene into Drosophila
that lacked the fly version of the gene (lats) prevented tumor
formation. Flies with the human LATS1 gene did not show the
widespread tumors and early mortality caused by the non-functioning
lats gene, suggesting that the two genes have the same
function.
In addition, Xu and his colleagues uncovered evidence that
lats is a new kind of tumor suppressor that blocks a specific
stage of cell proliferation. "We believe this finding represents a
major advance in understanding cell cycle regulation, and thus cancer
biology, because these LATS molecules are a new type of negative
regulator for the enzymes that drive the cell cycle," said Xu. Thus, he
said, the finding hints that further explorations into the molecular
signaling machinery involving LATS1 may yield insights into
little-understood cancers and perhaps lead to new cancer therapies.
In another set of experiments, which were described in a second
paper in the February 1999 issue of Nature Genetics, Xu's team
disrupted the LATS1 gene in mice. The scientists found that mice
developed ovarian tumors, soft-tissue sarcomas and pituitary
disorders.
"This finding is important because it is the first example showing
that an invertebrate tumor suppressor is also a tumor suppressor in
mammals," said Xu. "This also suggests that some human cancers may be
caused by a mutation of the LATS1 gene, although the correlation
between mice and humans is not that good in terms of the types of
tumors caused by a particular mutation."
In a commentary on the two papers, cancer researcher Christopher
Kemp of the Fred Hutchinson Cancer Research Center in Seattle noted
that even though many tumor suppressor genes have been identified in
flies, they "had not gained broad acceptance or notice in the mammalian
cancer genetics community."
But the two papers by Xu and his colleagues, "take the study of fly
cancer to a new level," wrote Kemp in the February 1999 issue of
Nature Genetics. "These show, apparently for the first time,
that a gene functions as a tumor suppressor in both invertebrates and
vertebrates. In two fell swoops, the authors have thrust a previously
obscure fly mutation to the center of the cell cycle and mammalian
cancer."
A key to the experiments was Xu's team's technique for producing
"genetic mosaic" fruit flies. In such mosaics, researchers can
manipulate selected cells to give them two copies of a defective tumor
suppressor.
"These mosaic flies are like cancer patients, in that very few cells
possess mutated tumor suppressors, consequently developing tumors,"
explained Xu. "Most of the cells in both the flies' and the human
patients' bodies carry normal copies of these genes.
"We believe that with this new technique we have shown that just as
in many other aspects of biology, Drosophila will prove an
excellent model to study tumor development, and that the process in
flies will prove directly relevant to what happens in mammals,
including humans," said Xu.
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