Consider these pathogenetic features: genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. They must add up to cancer, mustn’t they? Well, maybe. According to a new study, they can also be found in atherosclerosis.
The similarities between atherosclerosis and cancer have been suspected for some time because in atherosclerosis, certain cells engage in phenotypic switching. That is, they transition to different cell types. In particular, the phenotypic switching of smooth muscle cells (SMCs) has been implicated in atherosclerosis. However, the characteristics of SMC-derived cells and the underlying mechanisms of the phenotypic switching of SMCs had remained poorly understood.
To study SMC-derived cells in atherosclerosis, scientists based at Columbia University Irving Medical Center and supported by the National Institutes of Health used a range of methods—including molecular, cellular, histological, computational, human genetics, and pharmacological approaches. The scientists also considered how the SMC transition could be targeted for therapeutic benefit.
The scientists presented their findings in Circulation, in an article titled, “Atherosclerosis Is a Smooth Muscle Cell–Driven Tumor-Like Disease.”
“SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell–like characteristics … Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models.”
The researchers found increased rates of DNA damage and genomic instability—two hallmarks of cancer—in the converted smooth muscle cells of atherosclerotic plaque when compared to healthy tissue. Genomic instability is the increased tendency for DNA mutations and other genetic changes to occur during cell division.
Probing further, the researchers also found that cancer-associated genes became more active as the SMCs were being reprogrammed into the cells that made up the plaque. Using a mouse model expressing a known cancer mutation accelerated the reprogramming and worsened atherosclerosis. Finally, treating atherosclerotic mice with the anticancer drug niraparib, which targets DNA damage, showed potential for preventing and treating atherosclerosis.
These findings could pave the way for the use of anticancer drugs to counteract the tumor-like mechanisms driving the buildup of plaque in the arteries, the major cause of cardiovascular disease.
“We saw that niraparib actually shrinks the atherosclerotic plaques in mice,” said Huize Pan, PhD, the first author of the study. At present, he is assistant professor of medicine at Vanderbilt University Medical Center.
Muredach Reilly, MD, the senior author on the study and a professor of medicine at Columbia University, explained that understanding the molecular mechanisms that are driving the transition of smooth muscle cells can provide opportunities to disrupt tumor-like pathways and change how the cell behaves, in turn preventing or slowing progression of atherosclerosis.
