Atherosclerosis is considered to be a lipoprotein-driven chronic inflammatory disease involving pathological activation of multiple cell types, including immune cells (such as T cells and macrophages), smooth muscle cells (SMCs), and endothelial cells. In recent years, there has been increasing evidence that the transition of SMCs to other cell types (i.e., phenotypic switching) plays an important role in the development of atherosclerosis and the prevention of complications, but what role SMCs and SMCs-derived cells (SDCs) play in this process is not fully understood.
Recently, a study published by Circulation found that atherosclerosis, especially SMCs phenotypic switching, has a striking similarity with tumor cell biology, and believes that atherosclerosis is a tumor-like disease driven by SMCs, opening up a new path for mechanism-based atherosclerosis prevention and treatment.
Atheherosclerosis, a tumor-like disease?
In this study, we used the SMCs lineage to track mouse and human tissues, and applied a series of methods including molecular, cellular, histology, computational, human genetics, and pharmacology to explore the characteristics of SMCs and SDCs in atherosclerosis.
The results showed that SDCs in mouse and human atherosclerosis exhibited a variety of tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, anti-apoptosis, aggressiveness, and activation of comprehensive tumor-associated gene regulatory networks.
The specific expression of the oncogenic mutant Kras G12D in SMCs accelerates the phenotypic switching of SMCs and exacerbates atherosclerosis.
In addition, the study provided a proof of concept that niraparib, an antitumor drug that targets DNA damage repair, can attenuate atherosclerotic progression and induce regression of advanced disease lesions in mouse models.
The concept of "atherosclerotic oncology" was proposed, pointing out a new direction for basic and translational research in ASCVD
In fact, as early as 20 years ago, some scholars hypothesized that atherosclerosis is a tumor-like state of the arterial wall, and previous related studies also suggested that there may be a common molecular mechanism between atherosclerosis and tumors. In recent years, there has been increasing evidence that SMCs also drive the occurrence of atherosclerosis and dominate the lesion through phenotypic switching.
In view of the wide commonalities between SMCs conversion and tumor biology in atherosclerosis in terms of genomic instability, disease regulation, and anti-cancer therapy targeting DNA damage repair, as well as the atherosclerosis mechanism of clonal hematopoietic diseases that have recently emerged, this study proposes a comprehensive concept of "atherosclerotic oncology" as a new direction for basic and translational research in new cardiovascular diseases of atherosclerosis.
Fig.1 Conceptual model of "atherosclerotic oncology"Note: A. SDCs in atherosclerosis exhibit a variety of tumor cell-like features, including genomic instability, sustained proliferative capacity, anti-apoptosis, aggressiveness, and cancer stem cell-like features. Activation of a comprehensive tumor-associated gene regulatory network in SDCs. Oncogenic mutations, such as Kras G12D, can accelerate the phenotypic transition of SMCs and worsen atherosclerosis. Some cancer chemotherapy drugs (e.g., niraparib) may prevent/treat atherosclerotic cardiovascular disease (ASCVD). B. A broad conceptual model of "atherosclerotic oncology" has been proposed, in which somatic gene mutations in myeloid cells (clonal hematopoiesis of indeterminate potential) and vascular SMCs with DNA damage/somatic gene mutations may explain cell expansion and synergistically drive the progression of atherosclerosis.
Based on the mechanism of atherosclerosis, a new path of prevention and treatment is opened
This study further advances the study of prior DNA damage in atherosclerotic lesions by discovering widespread genomic instability in mouse and human atherosclerosis. Consistent with previous studies, this study suggests that genomic instability does not appear to primarily contribute to the senescence of SMCs, but rather a driver of the transformation of SMCs into SDCs cells.
In addition, the study also showed that the conditional expression of SMCs to the oncogene KrasG12D promoted oxidative DNA damage, accelerated SMCs phenotypic switching in mice, and exacerbated atherosclerosis. Recent studies have also suggested that various cells carrying DNA damage and somatic mutations may have complex cell-cell interactions that modulate disease progression and clinical cardiovascular events. In the future, a comprehensive assessment of somatic mutations in nonmyeloid cells such as SMC/SDC, endothelial cells, and fibroblasts in atherosclerotic lesions is critical.
This study suggests a wide range of similarities between SMCs transformation and tumorigenesis, suggesting that certain chemotherapy methods may have a preventive effect on atherosclerosis. In this setting, certain anticancer treatment strategies, including enhanced macrophage phagocytosis (e.g., anti-CD47 antibodies, siRNAs) and inhibition of cell proliferation (e.g., ATRA), have shown good arterial protection. Niraparib, an anti-tumor drug targeting DNA damage repair, may reduce the progression of atherosclerosis and induce regression of advanced disease lesions in mouse models, which has the effect of preventing and treating atherosclerosis.
Sotorasib, a selective inhibitor that targets KRASG12C mutations rather than KRASG12D mutations, has little effect on smooth muscle cell proliferation. Some anticancer therapies, including immune checkpoint inhibitors (eg, targeting PD1/PD-L1), can increase the risk of cardiovascular disease by stimulating cytotoxic T cells to secrete atherogenic cytokines. The conflicting effects of different types of anticancer therapies may reflect different molecular roles of specific cell types (e.g., T cells, macrophages, and SMCs/SDCs) in atherosclerosis, thus affecting the risk of clinical complications.
In addition, when considering anti-tumor therapies for ASCVD translational applications, each anti-tumor therapy strategy should be carefully evaluated preclinically, including side effects, safety, and efficacy. Focusing on the genetic (e.g., KRAS) and molecular (e.g., epidermal growth factor receptor signaling pathway) pathways that communicate between atherosclerosis and tumors, while defining the unique molecular and cellular processes in atherosclerosis, will reveal which anti-tumor treatment modalities or target intervention opportunities represent ASCVD, especially for those patients who still have a greater residual risk after lipid-lowering therapy.
医脉通编译自：Pan H, Ho SE, Xue C, et al. Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease. Circulation. 2024 Apr 30.
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