Lipid-Laden Macrophages and Inflammation in Atherosclerosis and Cancer: An Integrative View

Abstract

Atherosclerotic arterial plaques and malignant solid tumors contain macrophages, which participate in anaerobic metabolism, acidosis, and inflammatory processes inherent in the development of either disease. The tissue-resident macrophage populations originate from precursor cells derived from the yolk sac and from circulating bone marrow-derived monocytes. In the tissues, they differentiate into varying functional phenotypes in response to local microenvironmental stimulation. Broadly categorized, the macrophages are activated to polarize into proinflammatory M1 and anti-inflammatory M2 phenotypes; yet, noticeable plasticity allows them to dynamically shift between several distinct functional subtypes. In atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates within macrophages as cytoplasmic lipid droplets thereby generating macrophage foam cells, which are involved in all steps of atherosclerosis. The conversion of macrophages into foam cells may suppress the expression of given proinflammatory genes and thereby initiate their transcriptional reprogramming toward an anti-inflammatory phenotype. In this particular sense, foam cell formation can be considered anti-atherogenic. The tumor-associated macrophages (TAMs) may become polarized into anti-tumoral M1 and pro-tumoral M2 phenotypes. Mechanistically, the TAMs can regulate the survival and proliferation of the surrounding cancer cells and participate in various aspects of tumor formation, progression, and metastasis. The TAMs may accumulate lipids, but their type and their specific roles in tumorigenesis are still poorly understood. Here, we discuss how the phenotypic and functional plasticity of macrophages allows their multifunctional response to the distinct microenvironments in developing atherosclerotic lesions and in developing malignant tumors. We also discuss how the inflammatory reactions of the macrophages may influence the development of atherosclerotic plaques and malignant tumors, and highlight the potential therapeutic effects of targeting lipid-laden macrophages in either disease.

Inflammation, Microcalcification, and Increased Expression of Osteopontin Are Histological Hallmarks of Plaque Vulnerability in Patients with Advanced Carotid Artery Stenosis

“…These are significant players in the initiation and progression of atherosclerosis. The debris of macrophage-derived foam cells provides the major source of the necrotic core in the atherosclerotic plaque [ 26 ]. The liponecrotic tissue in atheroma with necrotic core appears to be developed by the structural collapse of the lipid core of atheroma due to the loss of elastic and collagen fibers; MFs are organically involved in this mechanism [ 27 ].…”

Cellular FXIII in Human Macrophage Derived Foam Cells

“…The triggering receptor expressed on myeloid cell-2, due their impaired cholesterol efflux capacity are lipid-laden cells, also resemble M2 phenotype. Macrophages are affected by a number of factors in the vessel wall which may influence their actual dynamic state of polarization [19].…”

Unravelling the role of obesity and lipids during tumor progression

“…Indeed, much evidence has suggested that macrophages can possess surface markers classically defined for both M1 and M2, and their phenotypes contribute to disease progression or improvement in a spatiotemporally dependent manner. In cancer, it is recognized that these global biochemical and metabolic aberrations generally lead to a pro-inflammatory polarization at the pro-tumor necroinflammation stage, and an anti-inflammatory polarization in the full-blown tumor ( Lee-Rueckert et al, 2022 ). The same also applies to ASCVD development ( Lee-Rueckert et al, 2022 ), where chronic inflammation leads to M1-like cholesterol ester accumulation and foam cell formation, followed by M2-driven remodeling before acute plaque rupture and thrombosis via inflammation again ( Sukhorukov et al, 2020 ; Wculek et al, 2022 ).…”