Mouse Study Suggests New Therapeutic Strategy To Reduce Cardiovascular Disease In Cancer Survivors

A mouse model of cardiotoxicity following DNA damage. (A) Schematic illustration of the experimental model of radiation-induced cardiotoxicity and a timeline of changes in cardiac physiology, cytology, and histopathology after RT. (B) LVEF of four irradiated mice and four sham-treated wild-type mice at 1 and 3 months post-treatment. Although LVEF was similar in irradiated and sham-treated mice 1 month after RT, LVEF decreased in all irradiated mice by 3 months after RT. N = 4 for each treatment condition, replicated twice. *P = 0.008, **P = 0.001, two-tailed Student’s T-test. (C and D) TUNEL staining of left ventricular myocardium 30 hours (C) and 28 days (D) after RT or sham treatment. (E) Masson’s trichrome staining of the left ventricular myocardium of a mouse at 3 and 6 months after cardiac radiotherapy shows progressive accumulation of perivascular and interfibrillar collagen (blue) with fibrosis (arrows) versus sham-treated Sting compared to+/+ mouse. Scale bar = 50 μm. For each treatment condition and time point, experiments were performed with N = 4 mice; representative images shown, in duplicate. Credit: Journal of Experimental Medicine (2022). DOI: 10.1084/jem.20220809

Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York have discovered that common cancer treatments, such as radiation or anthracyclines, activate key inflammatory signaling pathways that cause long-term damage to heart tissue.The study was published in Journal of Experimental Medicine (jem), showing that inhibiting this pathway can reduce the chances of developing heart disease later in life in cancer survivors.

Many cancers are treated with radiation and/or drugs that kill tumor cells By causing breaks in their DNA. But these treatments also damage the DNA of patients’ healthy cells. As survival rates for cancer patients continue to rise, its long-term consequences are of increasing concern.

For example, radiation therapy or a class of DNA-damaging drugs called anthracyclines may have delayed toxic effects on the heart, increasing the risk of cardiovascular disease, including coronary artery disease or heart failure. Long-term survivors of Hodgkin lymphoma have five times the rate of cardiovascular disease compared with the general population, a study has found.

“Mechanisms of late tissue toxicity after years of DNA damage cancer treatment Little is known about this,” said Adam M. Schmitt, a radiation oncologist at MSKCC. “Determining the pathogenic mechanism of toxicity and its activation of early biomarkers will provide an opportunity to intervene in therapy to prevent toxicity. “

In their study, Schmitt and colleagues found that one month after mice were exposed to radiation or anthracyclines, a specific population of heart cells called fibroblasts activated a set of genes that promote the link with pathological disease. Recruitment of various immune cell types associated with inflammation and tissue fibrosis. Within 3-6 months, the mice showed signs of cardiac dysfunction, and by 12 months, many of them had died of heart failure.

The researchers determined that this pathological process is driven by an immune signaling pathway called the cGAS-STING pathway.This pathway normally promotes an inflammatory response in response to pathogenic bacteria or viruses, but Schmitt and colleagues reasoned that it might also be activated by DNA fragments produced by radiation or anthracycline treatment.

Mice lacking the cGAS or STING proteins are protected from the toxic side effects of DNA-damaging cancer treatments. They showed no signs of heart inflammation, their hearts remained functioning normally, and they were alive a year after treatment. Small-molecule inhibitors of STING proteins also protect mice from Toxic effect Radiation therapy or anthracyclines.

through learning breast cancer patients Schmitt and colleagues found evidence that the cGAS-STING pathway may play a similarly important role in human cardiotoxicity following anthracycline treatment. One of the key inflammatory proteins induced by cGAS–STING signaling is CXCL10, and the researchers found that patients with the greatest increases in CXCL10 levels after anthracycline treatment subsequently showed changes associated with cardiotoxicity on echocardiography.

“Overall, our data suggest that targeting the cGAS–STING pathway has great potential as a therapeutic approach to prevent cardiac complications of DNA-damaging cancer therapy,” Schmitt said. “These data show Clinical Trials The use of cGAS–STING inhibitors to prevent cardiovascular disease after DNA-damaging cancer therapy is warranted. “

More information:
Achraf Shamseddine et al, Innate immune signaling drives late cardiotoxicity after DNA-damaging cancer therapy, Journal of Experimental Medicine (2022). DOI: 10.1084/jem.20220809
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Mouse study suggests new therapeutic strategy to reduce cardiovascular disease in cancer survivors (2022, December 19)
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