Caveolin-1 in Human Disease: The Roles of Caveolin-1 in Cancer and Atherosclerosis
Cancer and atherosclerosis are the two leading causes of morbidity and mortality in Western countries. Cancer disease is the uncontrolled growth of abnormal cells in various sites of the body such as breast, and one cardiovascular disease, coronary artery disease, involves the development of lipid and cellular deposits, also called atherosclerosis that can occlud blood flow to the myocardium. Caveolae are 50-100 nm cell surface plasma membrane invaginations that play a role in the regulation of cellular signaling and transport of molecules. Caveolae are enriched in sphingolipids, cholesterol and are characterized by the presence Caveolin-1 (Cav-1) protein. Cav-1 is expressed in most cells involved in atherosclerosis and cancer. Data from our group and others have shown that Cav-1 plays an important role in modulating these diseases. Here, we isolated bone marrow cells from Cav-1 (-/-) deficient mice to study the role of Cav-1 protein in the two diseases independently. Loss of Cav-1 in human breast cancer stroma is associated with tumor recurrence, lymph-node metastasis, and poor clinical outcome. Our results suggest that loss of Cav-1 is a robust biomarker for the “Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “The Reverse Warburg Effect”. In this model, we propose that loss of Cav-1 in cancer associated fibroblasts leads to autophagy/mitophagy and production of recycled nutrients (i.e. ketone, pyruvate, lactate). These recycled nutrients “fuel” the anabolic growth of cancer epithelial cells. Thus, the energy transfer from tumor stroma to the epithelial cancer cells represents a true host-parasite relationship. We have termed this new paradigm “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism”. In the second study, the role of macrophages in atherosclerosis was studied using bone marrow transplantation experiments. Current literature suggests a pro- or anti-atherogenic role for Cav-1 in this disease depending on the cell type examined. Our results suggest an anti-atherogenic role for macrophage Cav-1, since macrophages lacking Cav-1 are associated with increased lesion formation. In contrast, the presence of Cav-1 in endothelial cells is pro-atherogenic, since it promotes LDL transcytosis and exhibits increased activation. Thus, the study of Cav-1 serves as a model for studying complex disease pathogenesis.
Pavlides, Stephanos, "Caveolin-1 in Human Disease: The Roles of Caveolin-1 in Cancer and Atherosclerosis" (2010). ETD Collection for Thomas Jefferson University. AAI3440252.