In his very recent review of the importance of stem-cell ideas to cancer research, Prof. John E. Dick, University of Toronto, Canada, (who kindly provided Science Watch with early access) notes that it is not just research articles and reviews but also funding bodies that are "making strong predictions that targeting CSCs (cancer stem cells) more effectively will lead to improved patient outcomes" (Blood, 112[13]: 4793-807, 2008). Indeed, there is a "breathless excitement" about this shift in thinking—though here, one suspects, Prof. Dick is trying to introduce a note of caution. His own special area of interest is in the leukemias, but it is research on a solid tumor that brings the Toronto group and also an Italian team into the Top Ten this time (#9, #10).

The notion that there might be CSCs is not new, and confirmation of their existence has been emerging. Both Catherine O’Brien (#9) and Lucia Ricci-Vitiani (#10) and their colleagues were trying to find out, for colon cancer, if all cancer cells have the potential to initiate and then sustain the growth of tumors or whether those properties are restricted to some identifiable subfraction of cells. If it is the latter, then that cell subset ought to be a good target for novel and better-directed treatments.

Using xenotransplantation into immunodeficient mice, O’Brien et al. found that all cells capable of initiating colon cancer were positive for the cell marker CD133 but not all CD133-positive cells possess this property. The cancer-initiating cells were more than 200 times as frequent in the CD133-positive subset than in unfractionated tumor cells (1 in 57,000). All the same, they were rare (1 in 262), so more refined studies are required to narrow down their identity. The Italian group’s methodology and conclusions are very similar.

CD133 must have seemed well-deserving of its 2008 designation in the Journal of Pathology as "molecule of the moment" (D. Mizrak, M. Brittan, M.R. Alison, J Pathol., 214[1]; 3-9, 2008). However, a paper in the Journal of Clinical Investigation last summer appeared to cast some doubt on the role of CD133 cells. The title says it all: "CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors" (S.V. Shmelkov, et al., J. Clin. Invest., 118[6]: 2111-20, 2008). Of course, the work highlighted in this issue of Science Watch (#9, #10) is not saying that only stem cells are expressing CD133; it is the number of locations where CD133 is expressed that is surprising in Shmelkov and colleagues’ report. In a balanced commentary on the Shmelkov et al. paper, Mark A. LaBarge and Mina J. Bissell, from the Lawrence Berkeley National Laboratory, California, (J. Clin. Invest., 118[6]:2021-4, 2008) note that metastatic cancer cells may behave differently, so the fact that such cells can initiate tumors even though they are CD133 negative may not be contradicting the findings of O’Brien, Ricci-Vitiani, and their colleagues.

Do differences in colon-cancer-inducing cells have prognostic value? Recent work (D. Horst, et al., Brit. J. Cancer, 99[8]:1285-9, 2008) suggests that they might, for CD133 anyway. Samples from 77 patients with colon cancer were divided into two groups, those highly positive for CD133 (more than 50% of cells positive) and those less positive. Survival analysis revealed that patients who were highly positive had a worse outcome.

A former deputy editor of The Lancet, Mr. David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, U.K.

Keywords: cancer stem cells, CSCs, John E. Dick, Catherine O’Brien, Lucia Ricci-Vitiani, colon cancer, CD133, stem cells.