Scientists have identified a population of human colon cancer stem cells that can initiate tumor growth and differentiate into mature tumors, according to two reports in Nature
. Two groups, working independently, showed that a subpopulation of CD133+ cells within the tumor, representing just a small fraction of the overall cancer mass, behave as cancer-initiating cells, with the ability to maintain themselves in culture in an undifferentiated state, initiate tumor growth after xenotransplantation in mice, and differentiate into cancers that are phenotypically indistinguishable from the original human tumor.
"This is for me a really exciting set of reports," said Jeremy Rich
, associate professor of medicine at Duke University in Durham, NC, who was not involved with either study. "The way they used the same marker to prospectively identify the cancer stem cells...really suggests that there's a lot of commonalities between these cancers, and that's important because the lessons we learn from one cancer can be applied to others."
The fundamental question is "Does every cell in the cancer have the same ability to keep the cancer going?" said John Dick
, Canada research chair and senior scientist, Division of Cell and Molecular Biology, University Health Network, Toronto. "What's becoming clear for some cancers is that not every cell does. In fact, only rare cells have that ability." Cancer stem cells have previously been identified in M Leukemia
and in breast, prostate, and brain cancers
. Stem cells from brain and prostate cancers have been shown to express the cell surface marker CD133.
In the current studies, teams led independently by Dick and Ruggero De Maria
, research director, Department of Hematology and Oncology, Istituto Superiore di Sanita, Rome, used CD133 to prospectively seek out colon cancer stem cells. The two teams found that CD133+ cells, which are rare in normal colon tissue, are more common in colon cancers. They then used transplantation into immunodeficient mice to demonstrate that some, though not all, of the CD133+ cells could induce tumor initiation. CD133 "is a marker that is inclusive of stem cells, but it's not exclusive," Dick said.
Cancer stem cells represent about one in 50,000 tumor cells overall, and one in 262 CD133+ cells, according to Dick's report
. De Maria hypothesized that the numbers are actually higher than that, as the assays used tend to underestimate the stem cells' frequency. De Maria's report describes a method to maintain these cells in culture, where the CD133+ cells grow as undifferentiated "tumor spheres" that can develop into tumors upon transplantation. "For us, it was very important to develop an in vitro assay, because if you are able to get a high number of these cells, you can perform a lot of studies, freeze the cells, [and] use them for further testing," explained De Maria.
, associate professor of surgery at the University of Toronto, who was not on either of the research teams, said the two studies are "important additional pieces in the puzzle that strengthens this idea of cancer stem cells."
According to Rich, though CD133 is a marker of cancer stem cells, it likely is not directly related to carcinogenesis per se. "CD133 is probably not terribly important to the biology of the tumor. It's more like racing stripes on a car - it helps you identify it as a racing car, but it doesn't make it go." Both Dick and De Maria are searching for additional cell markers that can be used to purify cancer stem cells to homogeneity.
Nevertheless, these cells, representing just two to three percent of the overall tumor, should be the focus of cancer therapies, according to De Maria. "They are the most dangerous cells. They make the tumors metastasize [and] they are the only ones that can proliferate forever." According to recent reports from Rich's lab, cancer stem cells also exhibit enhanced radiation resistance
and can promote tumor vascularization
Dick noted that one outstanding question is where these stem cells come from: are they the result of developmental regression of a differentiated cell, or of mutation to normal colon stem cells? His team is now working to understand the gene expression patterns that differentiate cancer stem cells from other cells. De Maria is using his in vitro assay to look for new diagnostics and therapeutics.
"We need to refocus our research approaches to understand these cells and specifically devise strategies to beat these cells," Dick said. "It's like dandelions in the back yard: You can cut the leaves off all you want, but unless you kill the root, it will keep growing back."
Jeffrey M. Perkel
Links within this article:
I. Weissman, M. Clarke, "Leukemia and cancer stem cells," The Scientist
, April 1, 2006.
P.B. Dirks, "Stem cells for brain cancer," The Scientist
, April 1, 2006.
Ruggero De Maria
C.A. O'Brien et al., "A human colon cancer cell capable of initiating tumour growth in immunodeficient mice," Nature
, published online Nov. 19, 2006, doi:10.1038/nature05372
L. Ricci-Vitiani et al., "Identification and expansion of human colon-cancer-initiating cells," Nature
, published online Nov. 19, 2006, doi:10.1038/nature05384
S. Bao et al., "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response," Nature
, published online Oct. 18, 2006, doi:10.1038/nature05236
S. Bao et al., "Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor," Cancer Res
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