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What flies tell us about cancer
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At the same time as the Wingless pathway was being elucidated in flies, medical investigators independently found that the APC gene (short for the medical condition "adenomatous polyposis coli") was one of its components. The APC gene is mutated in over 80% of human colorectal cancer patients. This observation created a novel perspective on the development of this cancer and opened new ways of understanding it. Colorectal cancer is the most common cause of cancer death in the Western population when smoking-related cancers are excluded. At least half of our population develops a colorectal tumor by the age of seventy.
The epithelium lining of the human intestinal system is a tissue that requires constant self-renewal. This is achieved through a population of stem cells. These stem cells give rise to progeny that differentiate and migrate towards the intestinal lumen, where they absorb nutrients and water. They die after a few days and are shed into the gut lumen. The proliferating stem cell population, however, has to evade this dead-end program of differentiation in order to maintain life-time supply of new intestinal cells.
It is the Wingless signal that sustains these stem cells and thus determines the equilibrium between differentiating and proliferating colon cells. The APC protein normally serves as a repressor of the Wingless signaling pathway. This repression is relieved when the Wingless protein binds to a recipient cell. In this case, signal transduction can occur and the cells remain stem cells. This situation is perfectly, yet fatally, mimicked by mutations in the APC gene.
Once such a mutation has occurred the affected cell will start to proliferate uncontrollably and give rise to cell clumps in the intestinal walls (polyps). These harbor a great risk of accumulating further mutations, of entering a malignant state and of developing into a colorectal tumor.
In order to inhibit polyp development, it is necessary to counteract the over-stimulating effect of an APC mutation on the Wingless signaling pathway. Repairing the mutant APC gene is technically not feasible, but it might be possible to switch off pathway components that are needed to relay the Wingless stimulus. The main activating component in the Wingless signaling pathway is called b-Catenin in humans or Armadillo in flies. Upon Wingless contact with the recipient cell, Armadillo is relieved from the APC-mediated repression and can then alter gene expression, activating the Wingless program. Armadillo does not carry out this step on its own, it requires accessory proteins. Two such proteins, "Legless" (which in humans is called BCL9) and "Pygopus", have recently been identified in Professor Konrad Basler's group at the Institute for Molecular Biology of the University of Zurich. Legless and Pygopus bind to Armadillo and possibly mediate interaction with an unidentified protein complex that is needed for efficient expression of Wingless responsive genes. As they both were shown to exist in humans, too, they might be adequate targets for the pharmacological treatment of colorectal cancer, by blocking their association with Armadillo. This would prevent Armadillo from altering gene expression, keeping the cells from proliferating endlessly.
This is only one recent example of how basic research provides insight into mechanism underlying disease, revealing potential tools for curing these diseases.
Thomas Kramps
Links:
Interactive Fly:
http://sdb.bio.purdue.edu/fly/aimain/1aahome.htm
National Cancer Institute: http://www.nci.nih.gov/ |
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Discovery of "Legless" and "Pygopus" |
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Find out how 'legless' and 'Pygopus' were discovered in the group of
Professor Basler at the University of Zurich.
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Publication: Kramps, T. et al. |
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Anonymous Reviewer:
"These elegant, focused and hypothesis-driven experiments, described with precision, clarity and logic, substantially advance our understanding of Wnt signaling"
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A Successful Technology Transfer Project |
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Professor K. Basler, together with other scientists, realized the potential of his findings and developed a business-plan. Their spin-off company, The Genetics Company, was founded in 1998 and became fully operational in May 2000.
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