Mar. 12, 2004 TORONTO (March 11, 2004) - A research team at The Hospital for Sick Children (Sick Kids) led by Dr. Howard Lipshitz has discovered that a protein previously linked to mammalian embryo implantation, as well as tumour metastasis, plays similar roles in fruit fly development. This research is reported in the featured article in the March 9, 2004 issue of the scientific journal Current Biology.
"We were surprised to find such high evolutionary conservation of the structure, expression and function of these proteins - called integrin and basigin - between flies and mammals, whose ancestors diverged over 500 million years ago," said Dr. Lipshitz, a senior scientist and head of the Developmental Biology Research Program at Sick Kids and a professor of Medical Genetics and Microbiology at the University of Toronto. "In mammals, if you mutate the basigin protein, the embryo can't implant, probably because the extraembryonic membrane cannot maintain close contact with the wall of the uterus. In flies, if you mutate the proteins, two different extraembryonic membranes fail to maintain contacts and the result is death of the embryo."
While fruit flies develop quite differently from humans, there is remarkable conservation of fundamental processes and the genes that control them. For example, two thirds of all known human disease genes are also present in fruit flies. "This cheap and tractable genetic system serves as a 'living test tube' in which to figure out the fundamental molecular basis of human development and disease," added Dr. Lipshitz, also the Canada Research Chair in Developmental Biology.
Dr. Bruce Reed, a research associate in Dr. Lipshitz's lab and the paper's lead author, serendipitously discovered the fruit fly basigin protein two years ago, while doing live imaging studies with the state-of-the-art confocal microscopes in the Sick Kids Research Institute's Imaging Facility acquired with support from the Canada Foundation for Innovation and the Ontario Innovation Trust. Looking for a marker that would enable him to see live cells - particularly those of the extraembryonic tissues - as they change their shape and motion, Dr. Reed saw the molecules that he would eventually identify as basigin. The molecules were attached to the membrane of the yolk sac, a placenta-like structure that feeds the fruit fly embryo.
When integrin and basigin molecules were depleted, the extraembryonic membranes could not establish close contacts, equivalent to mammalian embryos not implanting. In addition, Dr. Reed found that membrane contact was required for survival of the tissues. In mutants, the tissues fall apart and die. This has an exciting connection to tumour cell metastasis in humans. "When a tumour metastasizes, cells in fact have to decide to leave it and invade other tissues," said Dr. Reed. "Here, in flies, you have cells leaving the tissue, but their fate is instead, to die. All you need is something that prevents cells from dying when they leave the tissue and they would immediately become 'immortal' and invasive."
"If you think about how the placenta has to be formed it is an invasive process and must be regulated so that it doesn't behave like a metastatic tumour," said Dr. Reed. "The implication is that there is a fine balance between the good kind of invasion and the bad kind."
In mammals, basigin is expressed on the surface of 60 per cent of human gliomas, a type of nervous system tumour, and prior research has shown that the higher the level of expression of basigin the more invasive the tumour. Eventually, the research team may be able to model the molecular basis of metastasis using flies. The next steps involve the detailed study of the molecular biology of the tissue contact process and the 'metastatic' behaviour of the cells as they leave the tissue in mutants.
Other members of the research team included Dr. Ronit Wilk of The Hospital for Sick Children and Dr. Frieder Schöck of McGill University. This research was supported by the National Cancer Institute of Canada, the Canada Research Chairs Program, and The Hospital for Sick Children Foundation.
The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit http://www.sickkids.ca.
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