Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In surprising reversal, scientists find a cellular process that stops cancer before it starts

24.01.2019

Salk research shows that cellular recycling process, thought to fuel cancer's growth, can actually prevent it

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.


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

Credit: Salk Institute


From left: Adriana Correia, Joe Nassour, Jan Karlseder, Robert Radford, Reuben Shaw and Javier Miralles Fusté

Credit: Salk Institute

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, which appeared in the journal Nature on January 23, 2019, 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.

"These results were a complete surprise," says Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and the senior author of the paper. "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."

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.

Karlseder's 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," says Joe Nassour, a postdoctoral fellow in the Karlseder lab and the paper's first author. "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, 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 tumor-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 was by far the dominant mechanism of cell death in the group in crisis, where many more cells died.

The researchers then explored what happened when they prevented autophagy in the crisis cells. The results were striking: without cell death via autophagy to stop them, the cells replicated tirelessly.

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 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. (Once cancer has begun, blocking autophagy may still be a valid strategy of "starving" a tumor, as a 2015 study by Salk Professor Reuben Shaw, a coauthor on the current paper, discovered.)

Karlseder, who holds the Donald and Darlene Shiley Chair, adds, "This work is exciting because it represents so many completely novel discoveries. 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. This opens up a completely new field of research we are eager to pursue."

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.

###

Other authors included Robert Radford, Adriana Correia, Javier Miralles Fusté, Brigitte Schoell and Anna Jauch.

The work was funded by the European Molecular Biology Organization (EMBO), the Hewitt Foundation, the Paul F. Glenn Center for Biology of Aging Research, the Salk Institute Cancer Center (core grant P30CA014195), the National Institutes of Health (R01CA227934, GM087476, R01CA174942), the Donald and Darlene Shiley Chair, the Helmsley Foundation, the Auen Foundation and the Highland Street Foundation.

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Media Contact

Salk Communications
press@salk.edu
858-453-4100

 @salkinstitute

http://www.salk.edu 

Salk Communications | EurekAlert!
Further information:
https://www.salk.edu/news-release/in-surprising-reversal-scientists-find-a-cellular-process-that-stops-cancer-before-it-starts/
http://dx.doi.org/10.1038/s41586-019-0885-0

Further reports about: Biology DNA DNA damage Salk apoptosis autophagy cancerous cell death cellular process chromosomes genes telomeres

More articles from Life Sciences:

nachricht A study demonstrates that p38 protein regulates the formation of new blood vessels
17.07.2019 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht For bacteria, the neighbors co-determine which cell dies first: The physiology of survival
17.07.2019 | Technische Universität München

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Megakaryocytes act as „bouncers“ restraining cell migration in the bone marrow

Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.

Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...

Im Focus: Artificial neural network resolves puzzles from condensed matter physics: Which is the perfect quantum theory?

For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.

Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...

Im Focus: Extremely hard yet metallically conductive: Bayreuth researchers develop novel material with high-tech prospects

An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".

The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...

Im Focus: Modelling leads to the optimum size for platinum fuel cell catalysts: Activity of fuel cell catalysts doubled

An interdisciplinary research team at the Technical University of Munich (TUM) has built platinum nanoparticles for catalysis in fuel cells: The new size-optimized catalysts are twice as good as the best process commercially available today.

Fuel cells may well replace batteries as the power source for electric cars. They consume hydrogen, a gas which could be produced for example using surplus...

Im Focus: The secret of mushroom colors

Mushrooms: Darker fruiting bodies in cold climates

The fly agaric with its red hat is perhaps the most evocative of the diverse and variously colored mushroom species. Hitherto, the purpose of these colors was...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

Tracking down climate change with radar eyes

17.07.2019 | Earth Sciences

Researchers build transistor-like gate for quantum information processing -- with qudits

17.07.2019 | Information Technology

A new material for the battery of the future, made in UCLouvain

17.07.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>