Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor... Show moreMacrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy. Show less
Cardiovascular disease is the leading cause of death worldwide. The primary underlying pathology of cardiovascular disease is atherosclerosis. Atherosclerosis is a chronic, multifactorial disease... Show moreCardiovascular disease is the leading cause of death worldwide. The primary underlying pathology of cardiovascular disease is atherosclerosis. Atherosclerosis is a chronic, multifactorial disease in which lipid accumulates in the arterial wall, leading to a local inflammatory reaction and atherosclerotic plaque formation. Atherosclerotic disease develops largely asymptomatic over a lifetime. However, plaque rupture or erosion can cause the formation of a superimposed thrombus, blocking the flow of blood, and cause acute cardiovascular events such as myocardial infarction or ischemic stroke. Defects in cholesterol metabolism and hypercholesterolemia, which are major risk factors for atherosclerosis, have been shown to affect hematopoiesis, immune cell production and platelet counts and reactivity. Therefore, bone marrow cholesterol handling is an interesting target in the battle against cardiovascular disease, and acute cardiovascular events in particular. This thesis describes novel interactions between cholesterol metabolism and the production of immune cells and platelets, and its effects on atherosclerosis and atherothrombosis development. Show less
Excessive accumulation of cholesterol by macrophage-derived foam cells is one of the characteristic features of atherosclerotic lesion development. Macrophages not only play an important role in... Show moreExcessive accumulation of cholesterol by macrophage-derived foam cells is one of the characteristic features of atherosclerotic lesion development. Macrophages not only play an important role in the initiation of the early atherosclerotic lesion, during further progression of the lesions macrophages also contribute to the formation of a necrotic core, thereby affecting the stability of the atherosclerotic plaque. Especially in the initiation of atherosclerosis the balance between cholesterol influx and efflux in macrophages is of prime importance. This balance is maintained by scavenger receptors and ATP-binding cassette (ABC) transporters, which are key mediators for macrophage cholesterol homeostasis as they facilitate the influx and efflux of lipids. Macrophages are incapable of limiting the uptake of cholesterol by scavenger receptors, including scavenger receptor class A (SR-A) and CD36. Therefore, prevention of lipid accumulation in macrophages largely depends on cholesterol efflux pathways, mainly mediated by ABC transporters. Gaining more knowledge on macrophage lipid homeostasis is of prime importance for the development of new therapeutic strategies to prevent atherosclerotic lesion development or induce regression of existing lesions. The aim of the studies described in this thesis was investigation of the role of several ABC transporters and SR-BI in (macrophage) lipid metabolism and atherogenesis. Show less
