Just as plastic tips protect the ends of shoelaces and keep them from fraying when we tie them, molecular tips called telomeres protect the ends of chromosomes and keep them from fusing when cells continually divide and duplicate their DNA. But while losing the plastic tips may lead to messy laces, telomere loss may lead to cancer.
Salk Institute scientists studying the relationship of telomeres to cancer made a surprising discovery: a cellular recycling process called autophagy, generally thought of as a survival mechanism, actually promotes the death of cells, thereby preventing cancer initiation.
The work reveals autophagy to be a completely novel tumor-suppressing pathway and suggests that treatments to block the process in an effort to curb cancer may unintentionally promote it very early on.
Each time cells duplicate their DNA to divide and grow, their telomeres get a little bit shorter. Once telomeres become so short that they can no longer effectively protect chromosomes, cells get a signal to stop dividing permanently. But occasionally, due to cancer-causing viruses or other factors, cells don't get the message and keep on dividing. With dangerously short or missing telomeres, cells enter a state called crisis, in which the unprotected chromosomes can fuse and become dysfunctional, a hallmark of some cancers.
The research team wanted to better understand crisis, both because crisis often results in widespread cell death that prevents precancerous cells from continuing to full-blown cancer and because the mechanism underlying this beneficial cell death isn't well-understood.
To investigate crisis and the cell death that typically ensues, researchers used healthy human cells to run a series of experiments in which they compared normally growing cells with cells they forced into crisis. By disabling various growth-limiting genes (also known as tumor-suppressor genes), their group enabled the cells to replicate with abandon, their telomeres getting shorter and shorter in the process.
The work reveals that, rather than being a mechanism that fuels unsanctioned growth of cancerous cells (by cannibalizing other cells to recycle raw materials), autophagy is actually a safeguard against such growth. Without autophagy, cells that lose other safety measures, such as tumor-suppressing genes, advance to a crisis state of unchecked growth, rampant DNA damage, and often cancer.
Next the researchers plan to more closely investigate the split in cell-death pathways whereby damage to chromosome ends (telomeres) leads to autophagy while damage to other parts of chromosomes leads to apoptosis.