Mar. 19, 2007 Scientists have discovered a new type of cell that appears to play a role in the development of cancer -- a highly volatile, precancerous stem cell that can either remain benign or become malignant, depending upon environmental cues. The finding may help define the role of cancer stem cells in the growth and recurrence of the disease as well as offer new options for cancer prevention, detection and treatment.
Current cancer stem cell theory holds that tumors are comprised of a variety of cell types. Among them is a small subset of rather primitive cells that, like other stem cells in the body, are self-sustaining, self-renewing and multipotent, or capable of creating other types of cells and tissues. These cells are different from normal stem cells, however, in that injecting even as few as 100 of them into laboratory animals will cause cancer. Scientists have dubbed these cancer stem cells.
Cancer stem cells were first identified in leukemia, but they have also been found in breast, brain, colon and prostate cancers. Because they are rather unstable, they are notoriously tricky to isolate and describe. They are also resistant to virtually any kind of treatment, and some scientists believe they are the reason cancer recurs. Until now, no one has known how they arise.
But a team of scientists, led by Dr. Jian-Xin Gao, a researcher in the department of pathology at Ohio State University Medical Center, has identified a new set of cells he calls precancerous stem cells (pCSCs).
These cells share some of the characteristics full-fledged cancer stem cells have, but they are different in that they respond to distinct cell signals that determine their ultimate fate -- whether they will continue to grow into cancer or cancer stem cells, lie inactive or be eradicated by the body's immune system.
"These hybrid cells are very complex. They have properties of normal and abnormal stem cells, and do not always lead to cancer -- only some of the time, and under very specific conditions," says Gao, who is also a member of the Ohio State University Comprehensive Cancer Center. "These cells appear to be a whole new class of cells involved in the development of cancer."
The findings emerged from a study in which Gao and his colleagues were investigating tumor growth in mice. They discovered that some of the animals had lymphoma, and that several cell lines from those tumors carried a unique and provocative phenotype, or surface protein signature: They carried neither the Sca-1 or c-kit markers, hallmarks of normal bone marrow stem cells, nor the lineage markers most of the cancer cells had, but they did exhibit stem-like structure. The researchers suspected these unusual cells might be precancerous stems cells and designed several tests and experiments to find out more about them.
They selected three pCSC lines and injected them subcutaneously, intraperitoneally or intravenously into three groups of mice. The mice represented different levels of immune function: One group was comprised of severe combined immune deficient mice, a second group was composed of mice whose immune systems had been knocked out by radiation, but had been partially restored by an infusion of bone marrow cells; and the third group was made up of normal, healthy mice.
The results showed that the strength of the immune system affected whether or not the mice got cancer. The scientists found that the pCSCs, like normal stem cells, had the ability to create various types of benign cells in mice with healthy or recovering immune systems. These daughter cells, however, were likely to die, especially when they encountered signals to further differentiate -- a strong contrast to the behavior of normal stem cells.
"We thought this was an interesting development," says Gao, "because these precancerous cells were actually stopped from becoming malignant. We are calling this process 'differentiation-induced cell death,' a protective mechanism the body may invoke to prevent pCSCs from maturing into full-blown cancer stem cells."
It was a different story with the mice with impaired immune systems, however. In those animals, the pCSCs developed into solid tumors, developing additional mutations in different cell types as they grew and spread.
Additional experiments revealed that the piwil2 gene may exclusively regulate the process of pCSC development.
Gao says these data suggest some important characteristics of pCSCs.
"First, it appears that pCSCs require some sort of signal, or cue, from their immediate environment that directs them to become benign or malignant. Second, it seems clear that they can be detected and eliminated by a robust immune system when they are actively developing into cancer cells."
Cancer stem cell theory is still in its infancy, but Gao feels these findings, if validated by additional studies, point to a candidate population of precancerous cells that may one day be a valuable target for new drugs and treatments. "To cure cancer, we have to eliminate all potential malignant cells -- not just the ones within easy reach."
The study received grant support from a number of sources, including the American Cancer Society, the National Cancer Institute, the U. S. Army Chronic Myelogenous Leukemia Research Program and the National Institute of Child and Human Development.
Colleagues contributing to the study include lead author Li Chen, Rulong Shen, Yin Ye, Ying Wang, Yan Liu, Larry Lasky, Nyla Heerema, Allen Yates and Sanford Barsky, all members of Ohio State's Department of Pathology; Xingluo Liu, Wenrui Duan, Jing Wen, Jason Zimmerer, Danilo Perrotti and William Carson, from Ohio State's Comprehensive Cancer Center; Xin-An Pu from OSU's Center for Molecular Neurobiology; Haifan Lin, from Yale University; Keiko Ozato, from the National Institute of Child Health and Human Development; and Satomi Kuramochi-Miyagawa, and Toru Nakano from Osaka University, Japan.
Citation: Chen L, Shen R, Ye Y, Pu X-A, Liu X, et al (2007) Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation. PLoS ONE 2(3): e293. doi:10.1371/journal.pone.0000293
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