Of the many components in the cell thought to play a role in cancer, few have received more attention in recent years than an enzyme that has been dubbed a cellular fountain of youth.
Known as telomerase, the enzyme can prolong the typically finite lifespan of a cell-about 50 doublings for some human cells when grown in a test tube-by restoring the chromosome tips that progressively wear away with each round of cell division. Not surprisingly, immortality is a valuable asset to a tumor, and telomerase is found to be hard at work in more than 90 percent of human cancers.
But research showing that the enzyme promotes tumors in mice, whose chromosome tips never become critically short, has raised questions about whether telomerase's role in longevity sufficiently explains its association with cancer.
Now, the discovery of a second cancer-promoting function for telomerase may put an end to the controversy. Drs. Laura Smith and Hilary Coller, postdoctoral fellows in Dr. Jim Roberts's lab in the Basic Sciences Division, found that telomerase also can trigger cells to grow and divide by altering the activity of genes that govern these processes.
The finding could spur pharmaceutical companies to reconsider whether telomerase is a viable target for anti-cancer drugs.
"Drug companies became skeptical about developing drugs to interfere with telomerase based solely on the enzyme's ability to stabilize chromosome ends," said Roberts, an investigator of the Howard Hughes Medical Institute.
"The reason is because even if a drug successfully inhibited telomerase, cells in a tumor would still have many divisions to go through before the chromosomes became critically short and the tumor cells stopped growing. But a second telomerase function that is more immediately needed by cancer cells would make anti-telomerase drugs more attractive."
Functions of telomerase
Telomerase is an enzyme that prevents the ends of chromosomes, known as telomeres, from shortening each time a cell divides. Because of constraints in the cellular machinery that duplicates the chromosomes, an event that must occur prior to each cell division, each newly copied chromosome destined for a daughter cell has a small portion of DNA missing at its end. Eventually, the telomeres become critically short, at which point a cell ceases to divide.
Telomerase adds bits of DNA back to the chromosome ends during each division cycle. It is active in certain cells, such as stem cells, that must overcome their innate restriction on longevity. More recently, researchers have found that telomerase's lifespan-extending activity is switched on in many types of cancers.
To search for a second telomerase function, Smith and Coller added an active telomerase gene to laboratory cultures of human mammary epithelial cells. These cells line the milk ducts in the breasts and are the most common breast cells to become cancerous. Although these and all other normal human cells possess the genetic instructions to make telomerase, the native genes are switched on only in cells that divide indefinitely.
The researchers found that when telomerase was turned on in the breast epithelial cells, they no longer required the normal stimulatory molecules, called growth factors, in order to multiply.
Next, they looked at whether this telomerase-induced growth and division was accompanied by changes in gene expression. To do this, Smith and Coller used DNA microarrays, chips onto which bits of thousands of different genes are spotted. This enabled the researchers to monitor the expression of about 7,000 different human genes. Thanks to work from the Human Genome Project, the identity of each of these genes and in some cases, their functions, are known.
Genetic differences
They found that compared to normal cells, the cells with elevated levels of telomerase had 154 genes whose activity increased and 92 genes whose expression decreased. Of these, they chose for further study five up-regulated genes and seven down-regulated genes whose expression levels differed most dramatically and consistently from the levels observed in the cells without active telomerase.
Smith said that they were gratified to learn that many of these genes had previously described functions in cell growth and division.
"When we began these studies, it seemed logical that if telomerase had other functions in addition to maintaining chromosome ends, they would include regulating genes involved in cell proliferation," she said.
Such genes normally work either to trigger cell growth and division or to restrain it. Both types of genes work together in carefully orchestrated pathways to allow cells to respond to growth signals and to avoid the rampant growth characteristic of cancer.
One of the genes identified in the study whose level is elevated by telomerase makes a protein called epidermal growth factor receptor (EGFR), which triggers a cascade of growth-inducing genes upon stimulation by a growth factor. To prove that higher levels of EGFR are responsible for the cell's ability to proliferate without addition of external growth signals, Smith and Coller inhibited the function of EGFR. Doing so decreased the growth of the cells, lending support to the idea that telomerase-driven changes in gene expression leads to unregulated proliferation.
Unknown factors
As of now, the researchers don't understand how the telomerase enzyme modulates activity of the growth-control genes. Telomerase is thought only to work at the tips of chromosomes, and none of the genes identified in the study are located near chromosome ends. Also unknown is why telomerase has evolved to have the two functions, although Roberts offered speculation.
"Perhaps it reflects what happens inside stem cells, where telomerase is produced," he said. "When telomerase is turned on, a growth-promoting program likely also must switch on, and it might make sense for a cell to couple the two functions."
Roberts also said that while his lab's results could mean good news for pharmaceutical companies interested in anti-cancer drugs, they raise concerns about the safety of telomerase for certain other potentially therapeutic applications.
"Some companies have proposed using telomerase to engineer long-lived human tissues, such as skin, that could be used for transplantation," he said. "But these efforts were based on the supposition that maintaining telomeres is the only function of the enzyme. If telomerase is also causing cells to divide uncontrollably, it becomes less useful."
