I think a little recap of Hallmarks of Cancer 1-3 is in order before we move to #4
1) Sustained proliferative signaling: Cancer cells no longer require external signals to be stimulated to grow, often having on-off switches that are stuck in the on position.
2) Evading Growth Suppressors: The brakes of the system are broken and nothing slows down.
3) Evading apoptosis: This is programmed cell death when something is not supposed to be there or if there is a mistake in the cell. Cancer cells turn off this automated self destruct mechanism.
And this leads us to Hallmark #4, which is “Enabling Replicative Immortality.” There is an internal timekeeper in normal cells. Generally after 40-60 divisions, the cell goes into a state called senescence (Sa-Ness-Ens) which means it is in permanent cell cycle arrest and won’t ever divide again, but remains alive. How does a cell keep count of how many times it divides you may wonder? The ends of the chromosomes of each cell are capped by repetitive pieces of DNA called telomeres and each time a cell divides a little chunk of the telomere is lost. After 40-60 divisions, the end of the chromosome is now exposed and gets damaged which prompts the cell to say “hey my DNA is damaged” and a pathway is activated that puts the cell into senescence and hence the damaged DNA doesn’t get passed down to a new cell.
For those of you that are thinking..yeah but you told me DNA damage causes apoptosis in Hallmark #3! You’re not wrong. There are many types of DNA damage and different mechanisms exist to deal with the types of damage. Sometimes the damage can be repaired, sometimes it’s so bad it can’t be repaired and the cell undergoes apoptosis (or worse), and sometimes the cell just quiets down in senescence but it won’t ever divide again, thus no errors get passed on.
Even though a senescent cell is alive, it loses some of its function. Senescence is what accounts for the physiologic process of aging. In fact, when you look at the cells in culture, they even look old! They look flat and tired compared to younger cells that can still divide. (Sorry not a dig at my elders at all!)
There is no physiologic stimulus that can jump start a cell and get it out of senescence…but cancer cells…yeah they have mutations that make them immortal and never have to listen to the timekeeper.
#morethanfour #ChildhoodCancer365
