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A cell containing a certain mutation divides, and its daughter cells divide again. At some point down the line, one of the cell’s progeny acquires further mutations and begins to divide more rapidly. Later on, a mass of cells, descendants of the original cell, begins to threaten the life of the organism. When, during this progression, did the cancer begin? When did the tumor cells cross over from a premalignant state to malignancy? In which generation were the seeds of metastasis planted?
Through decades of cancer research, these questions have remained controversial, but a new technique developed at the Weizmann Institute may help scientists to sort out the progression of cancer from individual abnormal cells to full-blown cancer. Prof. Ehud Shapiro of the Biological Chemistry Department, and Computer Science and Applied Mathematics Department, together with doctoral students Dan Frumkin and Adam Wasserstrom and their colleagues, produced two complementary studies; the first describing a method of reconstructing a “family tree” for a cell in a larger organism such as a human, and the second reporting their findings when they applied this method to a cancer cell.
Like people, the more closely related cells are to each other, the more alike they are. As the branches of the lineage tree spread out over hundreds and even thousands of generations, the cells’ genetic make-up drifts when they acquire mutations (usually harmless) and pass them on to their offspring. In previous research, Shapiro and his team had realized that certain repeating sequences of DNA called microsatellites tended to accumulate mutations at a more or less steady rate, and these could be used to accurately determine how closely cells were related – that is, how many generations back they had a common ancestor.
In the first study, which appeared in PLoS Computational Biology, Shapiro and his team investigated several different cell lineages in mice. By feeding the DNA sequences of these microsatellites into computer analysis algorithms they had developed, they were able to compare the average depth of the various cell lineages. They found, for instance, that B cells – a type of immune cell – undergo cell division about once a day. Adult stem cells, by contrast, divide less frequently. Studies such as these may eventually help to answer such questions as: “Do neurons in the brain regenerate?” or “Are new eggs created in adult female ovaries?”
Shapiro and his team, in collaboration with Prof. Gideon Rechavi from the Sheba Medical Center and others, then decided to apply this method to reconstruct, for the first time, the lineage of a cancer cell. “Cancer is primarily a disturbance of cell growth and survival, and an aberrant growth pattern is perhaps the only property that is shared by all cancers. But because the initiation and much of the subsequent development of tumors occurs prior to diagnosis, studying the growth and spread of tumors seems to call for retrospective techniques, and these have been lacking until now,” says Shapiro.
Their research, which was featured on the cover of Cancer Research, was based on tumor cells extracted from a mouse lymphoma. The team’s findings showed that the cancer lineage had nearly twice as many branched generations as neighboring lung cells – that is, the rate of cancer cell division was almost double. They were also able to calculate the age of the tumor and characterize its growth pattern. More importantly, their analysis lent strong support to the hypothesis that cancer starts with mutations in a single cell of a mature organism.
Shapiro and his team intend to apply the method to answering some key questions in human cancers. They suspect, for instance, that the depth of the cancer cell lineage and other characteristics of the family tree may serve as prognostic markers, indicating the severity of the disease. They also plan to investigate whether chemotherapy targets cells with a specific lineage profile. Creating detailed family trees for different cancers may enable researchers to refine diagnostic tools and therapies and, eventually, to get right back to the roots of cancer.
Prof. Ehud Shapiro’s research is supported by the Clore Center for Biological Physics; the Arie and Ida Crown Memorial Charitable Fund; the Cymerman – Jakubskind Prize; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; the Henry Gutwirth Fund for Research; Sally Leafman Appelbaum, Scottsdale, AZ; the Carolito Stiftung, Switzerland; the Louis Chor Memorial Trust Fund; and the estate of Fannie Sherr, New York, NY. Prof. Shapiro is the incumbent of the Harry Weinrebe Chair of Computer Science and Biology.
Lineage on Display
This research was the subject of an exhibit and interactive video presentation at the American Museum of Natural History in New York over the summer. Three other museums associated with the Museum of Natural History also mounted the exhibit: the McClung Museum in Knoxville, the Great Lakes Science Center in Cleveland and Science World in Vancouver. Lineage on Display
More information on the Weizmann Cell Lineage Project can be found at: www.weizmann.ac.il/lineage
The interactive feature can be found on the AMNH Science Bulletins website: http://www.amnh.org/sciencebulletins/?sid=h.s.evolutionary_tree.20080728&src=b
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