Cellular recycling process stops cancer before it starts

Scientists at the Salk Institute for Biological Studies have found that a cellular recycling process, previously thought to fuel cancer’s growth, can actually prevent it. Their work has been published in the journal Nature.

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.

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.

Professor Jan Karlseder and his 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.

“Many researchers assumed cell death in crisis occurs through apoptosis, which along with autophagy is one of two types of programmed cell death,” said Joe Nassour, a postdoctoral fellow in the Karlseder lab. “But no-one was doing experiments to find out if that was really the case.”

To investigate crisis and the cell death that typically ensues, Prof Karlseder and Nassour 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 tumour-suppressor genes), their group enabled the cells to replicate with abandon, their telomeres getting shorter and shorter in the process.

To know which type of cell death was responsible for the major die-off in crisis, they examined morphological and biochemical markers of both apoptosis and autophagy. Although both mechanisms were responsible for a small number of cells dying in the normally growing cells, autophagy — generally thought of as a survival mechanism — was by far the dominant mechanism of cell death in the group in crisis, thereby preventing cancer initiation.

“These results were a complete surprise,” Prof Karlseder said. “There are many checkpoints that prevent cells from dividing out of control and becoming cancerous, but we did not expect autophagy to be one of them.”

The researchers then explored what happened when they prevented autophagy in the crisis cells and found that the cells replicated tirelessly without cell death via autophagy to stop them. Furthermore, when the team looked at these cells’ chromosomes, they were fused and disfigured, indicating that severe DNA damage of the kind seen in cancerous cells was occurring and revealing autophagy to be an important early cancer-suppressing mechanism.

Finally, the team tested what happened when they induced specific kinds of DNA damage in the normal cells, either to the ends of the chromosomes (via telomere loss) or to regions in the middle. Cells with telomere loss activated autophagy, while cells with DNA damage to other chromosomal regions activated apoptosis. This shows that apoptosis is not the only mechanism to destroy cells that may be precancerous due to DNA damage and that there is direct cross-talk between telomeres and autophagy.

The work thus reveals that, rather than being a mechanism that fuels unsanctioned growth of cancerous cells (by cannibalising other cells to recycle raw materials), autophagy is actually a safeguard against such growth. Without autophagy, cells that lose other safety measures, such as tumour-suppressing genes, advance to a crisis state of unchecked growth, rampant DNA damage and often cancer.

The work further suggests that treatments to block autophagy in an effort to curb cancer may unintentionally promote it very early on. That said, once cancer has begun, blocking autophagy may still be a valid strategy for ‘starving’ a tumour.

According to Prof Karlseder, the work has opened up “a completely new field of research we are eager to pursue”. The team thus plans to more closely investigate the split in cell-death pathways whereby damage to telomeres leads to autophagy while damage to other parts of chromosomes leads to apoptosis.

“This work is exciting because it represents so many completely novel discoveries,” Prof Karlseder said. “We didn’t know it was possible for cells to survive crisis; we didn’t know autophagy is involved with the cell death in crisis; we certainly didn’t know how autophagy prevents the accumulation of genetic damage.”

Image caption: Left: The 23 pairs of chromosomes of cells in which autophagy is functioning look normal and healthy with no structural or numerical aberrations (each colour represents a unique chromosome pair). Right: The chromosomes of cells in which autophagy is not functioning bypass crisis, revealing both structural and numerical aberrations, with segments added to, deleted from and/or swapped between chromosomes — a hallmark of cancer. Image credit: Salk Institute.

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