Scientists in the US examining how human melanoma , a deadly form of skin cancer, spreads in mice specially bred to be vulnerable to cancer, found that there was a higher proportion of tumor causing cells in cancerous tissue than had previously been assumed, overturning the “stem-cell” theory of cancer which proposes that a only a handful of specialized rogue cells is responsible for causing new tumors. They suggest that upgrading lab tests to be more sensitive to finding tumor-causing cells will find more of them.
The study was the work of researchers from the University of Michigan at Ann Arbor, and features as the cover article in the 4 December issue of the journal Nature.
A key question in the minds of many cancer scientists and specialists today is whether among all the cells within a human cancer, are there many or just a few that have the potential to cause new tumors? The answer to that question has vast implications not only for research but also for the development of treatments because if the answer is there are only a few then new drugs can be developed to target only the few but if the answer is there are many and they are widely dispersed in cancers, then targetting only a few could be disastrous.
A recent theory to emerge that supports the idea that there are only a few specialist rogue cancer cells with tumorigenic potential (the power to create new tumors) is called the stem-cell theory of cancer growth. This theory proposes that there are only a few very rare human cancer cells with the potential to cause tumors. Some studies, which transplanted human cancer cells into specially bred, non-obese, diabetic mice with severely impaired immune systems (called NOD/SCID mice), suggest the prevalence of tumorigenic stem cells could be between 0.1 and 0.0001 per cent of cancer cells.
However, the authors in this study wrote that studies using the NOD/SCID mice might have underestimated the prevalence of tumor causing cells. So they set up this study, using NOD/SCID mice whose immune systems were even weaker (they lacked the killer T and B cells for instance), which they described as “highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg -/-) mice”.
The results showed that this more highly immunocompromised mouse model increased the ability to detect tumorigenic cells in human melanoma by “several orders of magnitude”. The researchers used cancer cells taken from primary cancer sites (where the cancer started) and from metastatic sites (where the cancer had spread to) from 12 different volunteer patients. They found that 25 per cent of these unselected melanoma cells formed tumors in the new, more highly immunocompromised, mouse model.
In fact the researcers also carried out single-cell transplants into the new mice and found that an average of 27 per cent of unselected melanoma cells from four different patients formed tumors.
The authors concluded that by changing the mouse model it is possible to detect far more tumor-forming cells, showing that they are probably far more common in human cancers than we thought.
Commenting on the effect this study will have on the stem-cell theory of cancer cells, senior investigator Dr Sean Morrison, director of the Center for Stem Cell Biology at the University of Michigan Life Sciences Institute, said:
“I think the cancer stem-cell model will, in the end, hold up for some cancers.”
“But other cancers, like melanoma, probably won’t follow a cancer stem-cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells,” he added.
Morrison explained the detailed part of their investigation and its implications for the treatment of melanoma:
“The assay on which the field is based misses most of the cancer cells that can proliferate to form tumors. Our data suggest that it’s not going to be possible to cure melanoma by targeting a small sub-population of cells.”
He and his team concluded that previous research using NOD/SCID mice greatly underestimated the prevalence of tumor-forming melanoma cells, partly because the mice still had enough natural killer cells in their immune systems to wipe them out. But in the new mouse model the natural killer cells were eliminated creating more “permissive conditions” for the transplanted melanoma cells to thrive in.
Co-author Dr Timothy Johnson, a specialist in skin cancer and director of the University of Michigan melanoma program said:
“People were looking to the cancer stem-cell model as an exciting new source for the development of life-saving cures for advanced melanoma. Unfortunately, our results show that melanoma does not strictly follow this model.”
He said that as we research new treatments for melanoma we will have to consider that a higher proportion of cancer cells may need to be killed.
The researchers stressed that their findings do not wipe out the stem-cell theory; perhaps they do exist in some forms of cancer, but they are “probably much more common than people have been estimating,” said Morrison.
More than 8,000 Americans die of melanoma every year.
“Efficient tumour formation by single human melanoma cells.”
Elsa Quintana, Mark Shackleton, Michael S. Sabel, Douglas R. Fullen, Timothy M. Johnson, and Sean J. Morrison.
Nature 456, 593-598, 4 December 2008.
DOI:10.1038/nature07567.
Sources: Journal abstract, University of Michigan.
Written by: Catharine Paddock, PhD