Not all cancer cells can spread, researchers say
By Randolph E. Schmid, Associated Press, 2/25/2003
Researchers studying breast cancer have found that only a small percentage of the tumor cells are capable of moving on and creating new cancer elsewhere in the body, a discovery they hope will lead to ways to target the most dangerous cells.
Only between 1 percent and 15 percent of cancer cells were capable of forming new malignant tumors in a study done at the University of Michigan Comprehensive Cancer Center. The findings are reported in yesterday's online edition of Proceedings of the National Academy of Sciences.
''The first step was to identify the cells, the next step is to try to find out what makes them tick and then to target them with new therapies,'' said Dr. Michael F. Clarke, who led the team.
Tests showed that these cells were able to develop into various types of cells present in a tumor, somewhat like a stem cell can develop into any of a number of normal tissues in the body.
Like stem cells, these dangerous cancer cells ''make copies of themselves -- a process called self-renewal -- and produce all the other kinds of cells in the original tumor,'' Clarke said.
Similar cells have been identified in human leukemia, but these are the first to be found in solid tumors, Clarke said. He said the researchers plan to begin looking at other types of cancer to see if they also have similar danger cells.
Dr. Max S. Wicha, who was part of the research team, said the finding helps point the way to more effective treatments.
''What we are working on now is finding out what makes these tumor stem cells different from the other cells in a tumor,'' he said. ''Now that we can actually identify them, we can start developing treatments to specifically target and hopefully eliminate them.
''If we are to have any real cures in advanced breast cancer, it will be absolutely necessary to eliminate these cells,'' he said.
For women with cancer, ''for the first time, we can define what we believe are the important cells -- the cells which determine whether the cancer will come back or be cured,'' Wicha stated in a press release. ''Before this, we didn't even know there were such cells.''
''This is not a cure for cancer,'' Clarke emphasized. ''But it is a very promising lead, which will focus our efforts to try to find a cure for cancer.''
Dawn Willis, scientific program director for the American Cancer Society, said the findings are ''a very interesting observation, but it is still a long way from clinical usefulness.''
Clarke agreed that their work is some steps away from clinical use. He said they hope to find pathways to target the danger cells this year, but then finding the chemicals to attack those targets and developing ways to use them could take five to 10 years.
Still, said Willis, who was not part of the research team, ''they have made a critical observation'' in singling out the type of cells that seem to be able to spread the tumor.
The researchers used breast cancer cells removed from patients and sorted the cells into groups according to the proteins present on the surface of the cells. They then injected the cells into the mammary glands of mice.
The one cell type that consistently caused tumors to develop had a protein called CD44 and little or none of a protein called CD24, they reported.
''As few as 100 to 200 of these tumor-inducing cells, isolated from eight of nine tumors in the study, easily formed tumors in mice, while tens of thousands of the other cancer cells from the original tumor failed to do so,'' Clarke said.
The scientists repeated the experiment up to four times. First, 200 cells with the unique two-marker surface pattern were isolated from the original human tumor. When these cells produced a breast tumor in a mouse, they isolated 200 cells from it with those markers. These cells were then injected into another mouse to produce another tumor. Once again the tumor was harvested, tumor stem cells were separated, then injected into another mouse.
''Tumor cells with this particular surface marker pattern produced a new tumor in the next generation of mouse every time,'' Clarke said.
The University of Michigan has applied for a patent on the identity and function of tumor stem cells.
This story ran on page C7 of the Boston Globe on 2/25/2003.
[ cancer.med.umich.edu
The PNAS site doesn't seem to have this yet this morning, at least I could not find it -mfm]
United States Patent Application 20020119565
Kind Code A1
Clarke, Michael F. ; et al. August 29, 2002
--------------------------------------------------------------------------------
Isolation and use of solid tumor stem cells
Abstract
A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary gland of severely immunodeficient mice. Xenograft tumors have been established from mastectomy specimens of breast cancer patients. Furthermore, in the three tumors that we have tested, we have been able to make single-cell suspensions and transfer the tumors serially through immunocompromised mice. These improvements in the xenograft assay have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis. Antibodies against Notch4 reduced tumor cell proliferation and survival.
--------------------------------------------------------------------------------
Inventors: Clarke, Michael F.; (Ann Arbor, MI) ; Morrison, Sean J.; (Ann Arbor, MI) ; Wicha, Max S.; (Ann Arbor, MI) ; Al-Hajj, Muhammad; (Ann Arbor, MI)
[Could some kind soul point me to the simple man's guide relating Notch4 and CD44? - mfm :-)] |
