PANETH, STEM CELLS AND CANCER
On April 29 the IAS in Princeton, New Jersey (https://www.ias.edu/), hosted the latest in a series of annual meetings titled “The Governor’s Conference on Effective Partnering in Cancer Research” (http://www.cinj.org/education/2014-governors-conference-effective-partnering-cancer-research). The meeting is organized by Arnie Levine, director of The Simons Center for Systems Biology’ (http://www.sns.ias.edu/csb).
The first talk by Hans Clevers from the Hubrecht Institute (http://www.hubrecht.eu/research/clevers/) described the fascinating discovery that Lgr5 (GPR49), a signaling protein in the Wnt pathway (http://www.rndsystems.com/Pathway.aspx?p=15489&r=15433) is a marker of many, if not most, adult and tumor stem cells. Clevers took an historical approach showing how the Austrian biologist Joseph Paneth (1857–1890), first reported these interesting large cells in the base of the intestinal crypts and then a narrow, slim cell that lies between each Paneth cell. Bringing us up to date Clevers showed how the narrow slim cells are in fact Lgr5 positive stem cells supported by factors such as EGF, TGF-alpha, Wnt-3 and the Notch ligand DII4 secreted by the Paneth cells. He showed how it was possible to isolate a single Lgr5+ cell and grow it clonally. In 3-D matrigel culture this cell goes on to produce what is essentially a miniature gut, a small vesicular body budding structures that are similar to villi. The growth and differentiation of these structures, as in the gut in vivo, is regulated through Lgr5 by Wnt agonists (R-spondins) and stem cell-specific E3 ligases that downregulate Wnt receptors. Some very beautiful movies explaining the role of Lgr5 in gut epithelium differentiation, gut tumor formation and in stem cells in other locations, such as the liver, can be found here, http://www.hubrecht.eu/research/clevers/research.html.
So why is all this medically important? The single mantra ‘follow the money’ is an excellent place to begin rooting out the causes of corruption in society. We can invent a similar mantra, ‘follow the pathway’ for understanding cancer. Understanding the Wnt pathway may lead us to identify targets that are amenable to treatment, perhaps through chemical synthesis of new Lgr5 ligands – drugs that correct aberrations in downstream functioning of the Wnt5 pathway. One such aberration is already well known. The most common mutation in colon cancer is inactivation of APC, a component of the complex of proteins that downregulate the Wnt pathway.
NOTE: Why hold the meeting at the IAS? Although the IAS only supports theoretical science on its campus, Prof Levine, joint discoverer of the cell death regulator protein p53, also holds a professorship at the Robert Wood Johnson Medical School (Rutgers) where his research can be pursued at the bench. The Governor’s Conference is an excellent mixture of both the practical and the theoretical aspects of cancer biology.
