Modifications in Assay Design Increase Detectable Frequency of Tumorigenic Cells

How common is the tumorigenic potential or tumor promoting property in human cancers? For many years, cancer researchers have tried to answer the fundamental question whether all tumor cells are equally likely to cause new cancers.

A generally supported idea is that only a tiny subset of highly prolific cancer cells, dubbed cancer stem cells and estimated to be as few as one in a million, are capable in promoting tumors growth. The fact that these cells are distinguishable from other cancer cells is an important property that scientists would theoretically be able to exploit in designing new, targeted, therapies. Research on diverse cancers, including melanoma, seems to support the hypnotists that only rare human cancer cells form tumors when transplanted into non-obese diabetic/severe combined immunodeficiency mice.

But when a team of researchers from the Howard Hughes Medical Institute, Life Science Institute, Department of Internal Medicine, and the Center for Stem Cell Biology, at the University of Michigan, Ann Arbor, MI, looked at 50 different molecular markers found on the surface of the melanoma cells, they could not find differences between the tumor-causing cells and those that did not spawn tumors. Therefore, they concluded that scientists may have underestimated the frequency of tumorigenic human cancer cells, the extent of which is so far uncertain.

In the 4 December 2008 issue of Nature, the international weekly science journal, the researchers show that by modifying the design of an assay (including the use of more highly immunocompromised non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain-null mice), as many as 25%, or one in four, of the melanoma cells were able to reproduce. Furthermore, in single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumors. The authors therefore concluded that modifications to xenotransplantation assays increase the detectable frequency of tumorigenic cells and that they are common in some human cancers.

The researchers acknowledge that it is possible that cancer stem cells are simply more common in certain cancers. They expect that in some cancers, a cancer stem cell model will be more prevalent that in other cancers. The evidence for cancer stem cells in certain cancers is particularly convincing. But, as was reported in the same issue of Nature, researchers who report cancer stem cells in solid tumors should be wary about these results, and should repeat their experiments using techniques that could help transplanted human cells survive in mice. Otherwise, the reserachers conclude, it’s unclear whether they have detected a rare subset of cells that can propagate tumors – or simply a rare subset of human cells that can establish themselves in mice.

Click here for the PubMed abstract. Elsa Quintana, Mark Shackleton, Michael S. Sabel, et al., Efficient tumour formation by single human melanoma cells. Nature 2008 Dec 4;456(7222):593-8.