by Monya Baker
Two research teams follow cancer to its source
According to two papers published in Nature this month, colon cancer tumours originate from normal stem cells. Both studies show that, when a cell-signaling pathway is misregulated, rare stem cells within the small intestine initiate cancer.
Much cancer stem cell work sorts through human tumour cells and transplants them into mice to identify a subset capable of initiating tumours anew. Not only is this approach challenged by cross-species differences and other transplantation techniques, but also it does not identify the original 'bad apples' from which the cancerous cells arose. Now, working in genetically engineered mice, two teams of researchers have been able to find the source of these cells. Both systems track the formation of aberrant growths from the crypt stem cells of the small intestine.
Over 80% of human colon cancers show overactive Wnt signaling, and researchers led by Hans Clevers of the Hubrecht Institute in Utrecht, the Netherlands, genetically engineered mice so that Wnt signaling could be tied to other genes and selectively activated in adult mice. Moreover, once this genetic pathway was activated, cells and their progeny would stain blue. When this system was targeted to non-stem cells, including proliferating cells, carcinomas were found in fewer than one in five mice. When researchers targeted the intestinal stem cells by linking the system to Lgr5, a gene expressed in these cells (See Stem-cell supermarker makes its mark), adenomas became visible throughout the small intestine. After 36 days, so many tumours had grown so large that the mice had to be killed1.
Richard Gilbertson of St. Jude Children's Research Hospital in Memphis, Tennessee, used a similar genetic system, but tied activation of Wnt signaling to the surface marker prominin 1 (PROM1, also called CD133) rather than Lgr5 (ref. 2). Once cells began to express this marker, they and their descendents made yellow fluorescent protein even if the marker was subsequently downregulated. The researchers first showed that CD133 is expressed in intestinal stem cells. Its expression occurs with that of Lgr5. Moreover, contiguous marked cells flowed up from the 'crypts' where stem cells reside. Eventually, the entire small intestine was marked yellow. When Wnt signaling is activated, abnormal growth becomes obvious within 24 hours, says Gilbertson. "Within 60 days, the whole small intestine is a tumour; there's no small intestine left."
Though the genetic marking technique showed that all of the cancer cells arose from intestinal stem cells, both Clevers and Gilbertson found that only about 7% of the tumour cells still expressed the markers (Lgr5 or CD133) that identified them as stem cells. "It's very tempting to speculate that these are transformed cells that propagate the cancer," says Gilbertson.
Right now, however, Gilbertson is particularly interested in fingering the cells that originate other types of cancers. Both Clevers's and Gilbertson's systems employ genetic systems that trigger intestinal cancers (adenomatous polyposis coli and beta-catenin, respectively). "Beta-catenin is not an oncogene in every setting," says Gilbertson, "so the obvious thing is to test other alleles." Researchers using xenotransplant assays have found CD133 on both stem cells and cancer stem cells in other tissues. A huge question in cancer biology is sorting out whether cancers arise from healthy stem cells or from other cells that take on stem cell characteristics. The answer is likely to be different for different tumour types, but the ability to prompt cancer and follow cells in a mouse might provide a common starting point.
Source: Nature