Kristine M. Conner
University of Pennsylvania Cancer Center
Last Modified: October 24, 2000
A human cancer cell is the product of a series of genetic mutations that transform a normal cell into a progressively abnormal cell. Currently, it is impossible for researchers to retrace the complex series of steps that were actually involved in any given cancer cell's transformation-there are simply too many unknowns. So instead, cancer biologists have been trying to define their own series of genetic mutations that would successfully transform a normal human cell into a cancer cell in the laboratory. Achieving this goal could help us to better understand the signaling pathways in a human cell that are required for malignant transformation to occur.
In his Tuesday morning keynote address, Dr. Robert Weinberg of the Massachusetts Institute of Technology described his research team's efforts to do just that. He stressed that these efforts are meant to contribute to the larger challenge of "discerning the underlying rules, or commonalities, that govern tumor behavior." As a biologist, he is interested in mapping out the patterns of genetic mutation that are common to any transformation of normal cells into cancer cells. His team's success in defining a specific set of genetic mutations that can turn a normal human cell into a cancer cell in the lab represents an important step in that process.
The identification of cancer-promoting oncogenes and cancer-inhibiting tumor suppressor genes, Weinberg noted, has certainly been a major breakthrough. Mutations that give rise to oncogenes and damage usual tumor-suppressing proteins such as p53 help to explain why a cell keeps growing and ignores any signals from its surroundings to stop. What has been less well understood, however, is why these cells can, as Weinberg put it, "transcend the growth limitation imposed by the generational clock." In other words, how are they able to achieve cell immortality? Why are they able to grow indefinitely? Each normal cell is programmed in such a way that it limits itself to a certain number of replications. Its "descendant" cells are programmed in the same way. So how do cancer cells manage to overcome this limit?
The answer proved to be the key to Weinberg's eventual success in transforming a normal human cell into a cancer cell. Telomeres, which are structures that protect the ends of a cell's chromosomes, are essential to the life of the cell. Without them, the ends of the chromosomes fuse and the cell dies. In normal cells, these telomeres shorten with each division; therefore, after a certain number of divisions, they lose their ability to protect the ends of the cell's chromosomes, and the cell dies. Weinberg pointed out that cancer cells somehow are able to retain their telomeres, guaranteeing their own immortality. They do not go through the normal period of slowdown and death that replicating normal cells do. This led Weinberg and his colleagues to theorize that cancer cells were somehow able to gain access to the telomerase gene, which causes activity by the telomerase enzyme, which in turn elongates the telomeres on the cell's chromosomes, affording them protection indefinitely. As a result, the cell does not die.
Weinberg described how his team performed a series of experiments to test this hypothesis about the role of telomeres. They found that introducing the telomerase gene into normal cells just before they were about to die allowed these cells to replicate without limit. They also found that "shutting off" telomerase in cancer cells caused them to die rather rapidly. The conclusion? The telomerase gene is "indeed an essential part of the cancer cell's machinery," working along with tumor-promoting and suppressor genes.
Weinberg related how he and his team took all of this information and used it to transform normal human cells into cancer cells. By introducing the telomerase gene into a cell, essentially making it immortal, and then targeting oncogenes at the cell's p53 and Rb (retinoblastoma) tumor suppressor proteins, they found that they could indeed turn a normal cell into a cancer cell, he said. "These are the first genetically-defined human tumor cells," Weinberg noted, and therefore easier to study than the cells that make up a spontaneously occurring human tumor, for which the pathways of transformation are much too difficult to trace.
He explained that the discovery is important for two reasons. First, the telomerase gene opens up yet another possible target for anti-cancer therapy. And second, this moves us closer to the larger goal of converting cancer into a set of "ground rules" that can be used to define the disease process more clearly.
This area of Weinberg's research, like that of many biologists working to understand cancer at the molecular level, has focused on the single cancer cell. He noted that this trend has been the inevitable result of the complexity of the cancer cell itself. But he also stressed that he would like to see researchers "broaden their horizons," moving away from looking at the cancer cell in isolation and instead look at the tumor mass as a whole. Weinberg noted that a tumor also consists of "co-opted, recruited normal cells" that researchers cannot continue to ignore.
"We had to ignore them in the past because the complexity of the cancer cell was so great," he said, "but now we have to start integrating the behavior of tumor cells with normal cells." He expressed the hope that the field will move in this direction over the next decade, as well as spend more time looking at the process of angiogenesis (how tumors create their own blood supply) and invasion of normal tissue by cancer cells.