Cancer stem cells drive metastasis

A distinct subpopulation of cancer stem cells in pancreatic tumors governs metastasis and renders the tumor resistant to chemotherapeutics, according to a new report in the journal Cell Stem Cell. "This is a confirmation of what a lot of people have been talking about, the hypothesis that cancer stem cells are the source of metastasis," Jeremy Rich of Duke University Medical Center, who was not involved in the study, told The Scientist. Although the study focused on pancreatic cancer, he noted, it could apply to many other tumors as well. "The implications are much, much broader," he said. Recent research has suggested that some tumors, including breast, colon, brain, prostate, and most recently, pancreas, arise from a small subset of stem-like cells called cancer stem cells, which often are marked by the cell surface antigen CD133. These cells induce tumor formation and are often resistant to conventional therapies. Researchers assumed that some segment of these cells also drove metastasis, but this had remained unproven. In the current study, Patrick Hermann, a medical student in Christopher Heeschen's lab at Ludwig-Maximilians-University, Munich, and colleagues used both primary human tumors and immortalized cell lines to identify a small population of stem cell-like tumor cells that appeared to self-renew and to differentiate into other cells of the tumor. Marked by CD133, these cells were also resistant to conventional chemotherapeutics, providing a possible explanation for the poor survival prospects for those affected by this disease. The team then identified a subset of CD133+ cells, which also expressed the chemokine receptor CXCR4, at the tumor's interface with healthy tissue. When these cells were injected into mice, they formed both primary tumors and metastases. But when they were preincubated with antibodies to CXCR4 (or depleted of CXCR4+ cells), they remained tumorigenic but lost the ability to metastasize. "That shows the significance of the CXCR4 receptor in giving rise to metastases," Hermann concluded. The study "begins to put a definition on the cells responsible for metastasis," said John Dick of the University of Toronto, who was not a coauthor. "I expect that CXCR4 will play a role in metastasis of many other tumors," he added.According to Dick, who led one of two groups that identified colon cancer stem cells last year, the idea that CXCR4 determines whether a tumor can metastasize makes sense given the receptor's known role in blood cell migration. "There's a lot understood about how CXCR4 works in cell homing and trafficking, so to see that marker come up with these results is not surprising, but it is very satisfying," he said. The finding also makes sense in light of previous research suggesting a link between CXCR4 and metastasis, and the fact that the biodistribution of the receptor's ligand, SDF-1, overlaps common metastatic destinations, such as the lung, liver, bone marrow and lymph nodes, Dick told The Scientist.A study published earlier this year had identified cancer stem cells in pancreatic tumors using a different set of cell markers. "These populations do overlap, but they are not exactly the same," Hermann said.Rich and Dick both noted that the current study's reliance on immortalized cell lines means some experiments will need to be repeated using primary tumor cells, because the two models may differ in subtle ways. "The critical experiments to show the functional significance of the CD133/CXCR4-positive cells were done with cell lines. It would be much more satisfying to see that occurring in primary cells," said Dick.According to Hermann, the decision to use immortalized cell lines was a practical one: pancreatic tumors are small and fibrotic, making it difficult to acquire large numbers of cells. For now, he and his colleagues are working to identify compounds that might attack these metastasis-promoting cells. Jeffrey M. Perkel mail@the-scientist.comLinks within this article:P.C. Hermann et al., "Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer," Cell Stem Cell, 1:313?23, September 2007. http://www.cellstemcell.com/I. Weissman and M. Clarke, "Leukemia and cancer stem cells," The Scientist, April 1, 2006. http://www.the-scientist.com/article/display/23273/Jeremy Rich http://neurology.mc.duke.edu/Rich__Jeremy.43.0.htmlJ.M. Perkel, "Colon cancer stem cells identified," The Scientist, Nov. 20, 2006. http://www.the-scientist.com/news/display/36646/P.B. Dirks, "Stem cells for brain cancer," The Scientist, April 1, 2006. http://www.the-scientist.com/article/display/23276/C. Li et al., "Identification of pancreatic cancer stem cells," Cancer Res, Feb. 1, 2007. http://www.the-scientist.com/pubmed/17283135K. Lee, "Chemokines may be used in metastasis," The Scientist, Mar. 6, 2001. http://www.the-scientist.com/article/display/19504/John Dick http://www.uhnresearch.ca/researchers/profile.php?lookup=1468P. Loetscher et al., "Chemokines and their receptors in lymphocyte traffic and HIV infection," Adv Immunol, 2000. http://www.the-scientist.com/pubmed/10605606T. Toma, "Metastatic signals," The Scientist, Sept. 18, 2003. http://www.the-scientist.com/article/display/21597/

Cancer stem cells drive metastasis

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