Cancer cells are stressed out and it may be a good thing

By: Zeynep Kahramanoğlu

“DNA in just one of your cells gets damaged tens of thousands of times per day,” says Monica Menesini in a TED-Education talk, that’s nearly a “quintillion DNA errors [in your body] everyday.” How do our cells handle these mistakes? And how do cancer cells thrive off these mistakes?

Old Faithful DNA Replication?

In order to renew, replace, survive, and expand, our cells need to divide and replicate our DNA. 

Sometimes, DNA in our cells can become damaged, or the replication process can be done incorrectly. The cell can be damaged by external factors, such as ultraviolet light, radiation, and certain chemicals found in tobacco smoke, among other things. Cells can also be damaged by internal factors; an overproduction of hydrogen peroxide, for example, which is found naturally in the cell. Cells can also make mistakes during DNA replication, then fail to properly repair those errors, eventually leading to irreversible damage.

These mistakes and damages are a phenomenon known as “replication stress.” 

“Fortunately, your cells have ways to fix these problems, most of the time,” says Menesini. Normally, the repair machinery works to review and fix these errors, and your cells can tolerate more mistakes than you think, but in some cases, it can lead to major problems like cancer.

Unlike our normal cells, cancer cells have chronic replication stress. If a normal cell’s DNA has too many mistakes, it activates the body’s surveillance system, alerting your cells that something is wrong. The cell gets caught by this screening process, label themselves as ‘defective’, and kill themselves. In other words, to prevent passing on these mistakes to subsequent dividing cells, the defective cell will activate its own death. Because the more mistakes in your DNA, the more opportunities for mutations in your DNA. More mutations increases the probability of the cell to become cancerous.

Cancer cells can thrive off the chaos of these mistakes; they take advantage of it to make copies of themselves and have the ability of escaping the body’s screening process, ensuring their survival. If left unchecked, they eventually spread to other parts of the body.

Exploiting the Need and Greed of Cancer Cells

There is a downside for cancer cells: More mistakes means it takes longer for them to multiply, slowing down their takeover. “Replication is a double-edged sword for cancer cells,” write Scientists Pasero and Tourriere, but a phenomenon they rely on, nonetheless. 

“Replication stress is a double-edged sword for cancer cells,” write Scientists Pasero and Tourriere, but a phenomenon they rely on, nonetheless.

How do cancer cells keep their replication stress in check so that they can multiply too? In a recent paper from Molecular and Cellular Oncology, Pasero and Tourriere say it may be about the balance between these two genes found in our genetic code:

  1. CLASPIN – When normal cells get replication stress, CLASPIN is responsible for stopping the cell division process. Essentially, it’s the ‘cancel’ button. 
  2. TIMELESS – When normal cells get replication stress, TIMELESS is responsible for cell survival. It’s the ‘restart’ button. 

Many other researchers agree: It’s all about balance. Both CLASPIN and TIMELESS work as a team and screen DNA for mistakes. We need them for our normal cells, too. Too many mistakes? CLASPIN helps activate the ‘kill’ switch. Manageable fix? TIMELESS tells the cell to ‘try again’.

But Pasero and Tourriere think that cancer cells can manipulate these two important genes to their advantage. What’s more, CLASPIN and TIMELESS appear in above average levels in cancer cells. Cancer cells may be using these two genes to protect themselves, but that means that they also make ideal targets for anti-cancer therapies.

Scientists Ubhi and Brown believe that targeting the mechanisms of replication stress may be a “promising strategy as it provides a selective means of eliminating tumors,” revealing new ways for treatment. 

Strategies to exploit cancer cell dependence on this phenomenon involve cutting off the right balance of help from genes like CLASPIN and TIMELESS, as well as the use of replication stress-activating drugs. These drugs work by increasing stress – or stress overload – which forces cell death. 

These strategies, explain Ubhi and Brown, in combination with other therapies that target the system behind the body’s screening processes, “are already showing promise, and with the advent of powerful new technologies, both in academic and clinical settings, many more are likely to be revealed for therapeutic development.”

So for once, stress sounds like a good thing, and when it comes to cancer cells, may be worth exploiting.

Zeynep is a Research Technician in a tumor immunology lab. She has a BSc. in Molecular Biology and Genetics, and a MSc. in Pathology and Laboratory Medicine. She likes to unravel the mysteries of science, review new restaurants with amateur expertise, and learn new moves in dance class.

Resources

Gaillard, Garcia-Muse and Aguilera. Replication stress and cancer. Nature Review 15, 276-289 (2015). https://www.nature.com/articles/nrc3916

Menesini, Monica. “What happens when your DNA is damaged?” TED-Ed. 2015

Pasero P and Tourriere H. (2019) Overexpression of the Fork Protection Complex: a strategy to tolerate oncogene-induced replication stress in cancer cells. Molecular and Cellular Oncology 6:4, 1607455  DOI: 10.1080/23723556.2019.1607455

Ubhi and Brown. Exploiting DNA Replication Stress for Cancer Treatment. Cancer Research 79(8), 1730-1739 (2019). DOI: 10.1158/0008-5472.CAN-18-3631

Zeman and Cimprich. Causes and Consequences of Replication Stress. Nature Cell Biology 16(1): 2-9 (2014). DOI: 10.1038/ncb2897

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