Which cells need to be mutated in order for solid tumours to fully develop? Many have postulated that mutation of a normal tissue stem cell might be required for both tumour initiation and progression, whereas others have argued that mutations in progenitor cells can induce stem cell-like qualities, giving rise to long-lived and clinically manifest disease. Two papers recently published in Nature add thought-provoking data to this debate.
In order to examine whether PROM1 (also known as CD133) is a stem cell marker, Richard Gilbertson and colleagues have generated a knock-in mouse that expresses tamoxifen-regulatable Cre recombinase and a nuclear LacZ marker from the Prom1 locus (Prom1C-L). Prom1 is null in Prom1C-L/C-L mice and these animals develop normally, indicating that the gene is not required for development. Unlike other tissues in the Prom1C-L-heterozygous mice, PROM1 expression was restricted to the stem cell compartment in the small intestine. The distribution of Prom1 and Lgr5 overlapped: 75% of Lgr5 mRNA-positive cells in Prom1+/C-L mice also expressed nuclear LacZ. Crossing Prom1+/C-L mice with Cre-dependent Rosa26 yellow fluorescent protein (YFP)-expressing mice, thereby constitutively activating YFP in PROM1-expressing cells and their progeny after injection of tamoxifen, showed that PROM1 cells can give rise to all cells of the small intestinal epithelium. Crossing these mice with mice expressing an inducible oncogenic form of β-catenin resulted in tumour formation in these animals. Interestingly, only 7% of the cells within these tumours remained PROM1-positive; the authors suggest that these might be a subpopulation of transformed stem cells.
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