Theory which states that all cancer cells are mortal is proved wrong. Scientists at the Salk Institute for Biological Studies have uncovered an important clue to one of the mechanisms that underlies cancer cell immortality.
In stark contrast to normal cells, which only divide a finite number of times before they enter into a permanent state of growth arrest or simply die, cancer cells never cease to proliferate.
AdvertisementTheir findings revealed that an unanticipated structure at chromosome ends, which could be a key ingredient in the biological "elixir of life," potentially making it an attractive chemotherapeutic target to cut short the life of a cancer cell.
"How tumor cells evade cell death is still baffling to us, but we think we may have solved a small piece of this puzzle," said Jan Karlseder, a professor in the Molecular and Cell Biology Laboratory, who led the Salk team.
A lynchpin to the immortality of malignant cells is the ability to maintain telomeres, the specialized ends of chromosomes. Like slow-burning fuses, telomeres become shorter each time a cell divides, acting as a kind of cellular clock ticking down a cell's age. Eventually they are depleted, and the cell enters a permanently arrested state called senescence. To escape this inevitable demise, about 90 percent of human tumors rely on a huge boost in the levels of an enzyme called telomerase, which adds DNA to telomeres, thus turning the clock backwards.
The remaining 10 percent use a mechanism known as alternative lengthening of telomeres (ALT).
"Although it is a rare phenomenon, understanding ALT is essential since tumors can evade anti-cancer therapies aimed at inhibiting the activity of telomerase through the activation of ALT," explained postdoctoral researcher and first author Liana Oganesian.
"This is why we clearly need a two-pronged approached to successfully tackle cancer," added Oganesian.
Unlike telomerase, which tacks on telomeric DNA, ALT replenishes chromosome ends through a process called homologous recombination. In normal cells homologous recombination is used to mend broken DNA, whereby the intact neighboring DNA of an identical sequence is used as a template to restore the sequence of the broken DNA piece. Uniquely, human ALT tumors make use of the same recombination machinery to illicitly restore lost telomeric DNA, but not much is known about this process.
Trying to learn more about the biological tools that ALT tumors use to sustain their immortal status, Karlseder and his team uncovered a new structural beacon, called the C-tail-a string of DNA rich in the base cytosine (c) that hangs over the very tip of telomeres. The finding came as a big surprise since conventional wisdom had it that mammalian cells normally terminate both ends of every chromosome with a single-stranded stretch of DNA rich in the base guanine (G).
When Ogenesian carefully looked at chromosome ends, however, she discovered that about half of all telomeres in ALT tumors bore a C-tail, while the presence of such a tail in normal human cells was several hundred fold less prevalent.
"This piece of DNA is conspicuously absent in tumors that use telomerase, suggesting that C-tails are a unique feature of ALT tumors," she said.
The study is detailed in the issue of Molecular Cell.