Cancer-associated fibroblasts (CAFs) and plaque-associated fibroblasts (PAFs): Unraveling the cellular crossroads of atherosclerosis and cancer

Faa, Gavino;Ziranu, Pina;Pretta, Andrea;Cau, Flaviana;Castagnola, Massimo;Spanu, Dario;Saba, Giorgio;D'Agata, Alessandra Pia;Tiwari, Ekta;Suri, Jasjit S;Scartozzi, Mario;Saba, Luca

2025-01-01

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Abstract

Atherosclerosis is a complex process involving various cells and molecules within the atherosclerotic plaque. Recent evidence suggests that plaque-associated fibroblasts (PAFs), also known as atherosclerosis-associated fibroblasts (AAFs), might play a significant role in the development and progression of the disease. The microenvironment of the atherosclerotic plaque, resembling the tumor microenvironment (TME), includes various cellular populations like plaque-associated macrophages (PAMs), plaque-associated neutrophils (PANs), vascular smooth muscle cells (VSMCs), myeloid-derived suppressor cells (MDSCs), and PAFs. Similar to cancer-associated fibroblasts (CAFs) in tumors, PAFs exhibits a wide range of characteristics and functions. Their interactions with endothelial cells, smooth muscle cells, and other stromal cells, including adventitial fibroblast precursors, significantly influence atherosclerosis progression. Moreover, the ability of PAFs to express various markers such as alpha-SMA, Desmin, VEGF, and GFAP, highlights their diverse origins from different precursor cells, including vascular smooth muscle cells, endothelial cells, glial cells of the enteric nervous system, adventitial fibroblast precursors, as well as resident and circulating fibrocytes. This article explores the molecular interactions between PAFs, cells associated with atherosclerosis, and other stromal cells. It further examines the role of PAFs in the development and progression of atherosclerosis, and compares their features with those of CAFs. The research suggests that studying tumor-associated fibroblasts can help understand fibroblast subpopulations in atherosclerotic plaque. Identifying specific subpopulations could provide new insight into atherosclerosis complexity and lead to the development of innovative drugs for medical intervention.