Annuaire
M. Philippe Frank
Coordonnées
Thèmes de recherche
Plasma Lipoproteins, Cholesterol Homeostasis, and Human Diseases
Cholesterol and Cancer
Many studies have now suggested an important role for several dietary nutrients in the progression and development of breast cancer. However, few studies have specifically addressed the role of cholesterol as an important factor involved in breast cancer progression. Understanding the correlation between plasma cholesterol and tumor development is important for a better comprehension of the risk factors associated with cancer development. Epidemiological studies have suggested that high plasma cholesterol levels are associated with increased risk of mortality and increased risk of postmenopausal breast cancer. In pre-menopausal women, recent report have proposed a protective role for high-density lipoprotein (HDL) against breast cancer. However, it appears that in advanced stages of breast cancer, plasma cholesterol levels are reduced compared to those of healthy controls. A role for cholesterol in breast cancer is consistent with studies showing that the use of lipid-lowering drugs in older women is associated with reduced breast cancer development. Older studies have even observed that tumor progression was associated with a progressive decrease in plasma cholesterol levels. Therefore, decreased plasma cholesterol levels appear to be a metabolic consequence of cancer. Taken together, these data suggest that increased plasma cholesterol levels may be a predisposing factor for cancer development, but in later stages of cancer development, plasma cholesterol levels are reduced possibly due to an increased utilization by the tumors. Finally, we also need to consider the possibility that breast cancer in pre-menopausal and post-menopausal women may have different susceptibility to increase plasma cholesterol and increase lipoprotein levels.
It is therefore essential to understand the molecular mechanisms that are associated with cholesterol-mediated regulation of the tumorigenic process. Therefore, our project are aimed at understanding the role of cholesterol in breast cancer progression and its utilization by tumors. This aspect is critical for the understanding and to reconcile some of the apparently contradictory findings described above and in the literature.
Lipoprotein, Cholesterol and Atherosclerosis
Caveolae are 50-100 nm cell surface plasma membrane invaginations observed in terminally differentiated cells. They are characterized by the presence of the protein marker caveolin-1. Caveolae and caveolin-1 are present in almost every cell type that has been implicated in the development of atherosclerosis. These include endothelial cells, macrophages, and smooth muscle cells. Caveolae and caveolin-1 are involved in regulating several signal transduction pathways and processes that play important roles in atherosclerosis.
Heart disease is a leading cause of death in the United States and the Western World. A deep understanding of the events leading to heart disease is necessary in order to prevent and properly treat this deadly illness. one important clue is the role of fat and especially cholesterol in this process. High blood cholesterol levels are a major risk factor for heart disease, and the underlying disease process --more broadly termed atherosclerosis.During this process, the "bad" cholesterol is deposited in the blood vessels, leading to the formation of a blockage. Ultimately, we must understand the mechanisms by which occlusions form to prevent their development. Recent studies using genetically-engineered mice (Cav-1(-/-) knock-out animals) have now clearly demonstrated a role for caveolin-1 and caveolae in the development of atherosclerosis. In fact, they suggest a rather complex one, either pro-atherogenic or anti-atherogenic, depending on the cell type examined. For example, in endothelial cells, caveolin-1 and caveolae may play a pro-atherogenic role by promoting the transcytosis of low-density lipoprotein (LDL) particles from the blood to the sub-endothelial space. In contrast, in smooth muscle cells, caveolin-1's ability to negatively regulate cell proliferation (neointimal hyperplasia) may be anti-atherogenic. In addition, macrophage caveolin-1 may have a protective effect by preventing cholesteryl ester accumulation in macrophages.
Industrial Relevance: Our work may lead to the development of new therapeutics for the treatment of cancer and vascular diseases.
Publications PubMed Link For Frank PG