Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders.

Here we review the clinical and translational implications of the caveolin gene family for understanding the pathogenesis of human diseases, including breast and prostate cancers, pulmonary hypertension, cardiomyopathy, diabetes, and muscular dystrophy. Detailed phenotypic analysis of caveolin knockout mice has served to highlight the crucial role of a caveolin deficiency in the pathogenesis of many human disease processes. Mutations in the human caveolin genes are associated with a number of established genetic disorders (such as breast cancer, lipodystrophy, muscular dystrophy, and cardiomyopathy), making the caveolins important and novel targets for drug development. The implementation of new strategies for caveolin replacement therapy-including caveolin mimetic peptides-is ongoing

Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: Similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling"

Caveolin-1 (-/-) null stromal cells are a novel genetic model for cancer-associated fibroblasts and myofibroblasts. Here, we used an unbiased informatics analysis of transcriptional gene profiling to show that Cav-1 (-/-) bone-marrow derived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers. More specifically, the transcriptional profiles of Cav-1 (-/-) stromal cells were most closely related to the primary tumor stroma of breast cancer patients that had undergone lymph-node (LN) metastasis. This is consistent with previous morphological data demonstrating that a loss of stromal Cav-1 protein (by immuno-histochemical staining in the fibroblast compartment) is significantly associated with increased LN-metastasis. We also provide evidence that the tumor stroma of human breast cancers shows a transcriptional shift towards oxidative stress, DNA damage/repair, inflammation, hypoxia, and aerobic glycolysis, consistent with the "Reverse Warburg Effect". Finally, the tumor stroma of "metastasis-prone" breast cancer patients was most closely related to the transcriptional profiles derived from the brains of patients with Alzheimer's disease. This suggests that certain fundamental biological processes are common to both an activated tumor stroma and neuro-degenerative stress. These processes may include oxidative stress, NO over-production (peroxynitrite formation), inflammation, hypoxia, and mitochondrial dysfunction, which are thought to occur in Alzheimer's disease pathology. Thus, a loss of Cav-1 expression in cancer-associated myofibroblasts may be a protein biomarker for oxidative stress, aerobic glycolysis, and inflammation, driving the "Reverse Warburg Effect" in the tumor micro-environment and cancer cell metastasis

Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome

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

Caveolae and transcytosis in endothelial cells: Role in atherosclerosis

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Role of caveolin-1 in the regulation of lipoprotein metabolism

Lipoprotein metabolism plays an important role in the development of several human diseases, including coronary artery disease and the metabolic syndrome. A good comprehension of the factors that regulate the metabolism of the various lipoproteins is therefore key to better understanding the variables associated with the development of these diseases. Among the players identified are regulators such as caveolins and caveolae. Caveolae are small plasma membrane invaginations that are observed in terminally differentiated cells. Their most important protein marker, caveolin-1, has been shown to play a key role in the regulation of several cellular signaling pathways and in the regulation of plasma lipoprotein metabolism. In the present paper, we have examined the role of caveolin-1 in lipoprotein metabolism using caveolin-1-deficient (Cav-1−/−) mice. Our data show that, while Cav-1−/− mice show increased plasma triglyceride levels, they also display reduced hepatic very low-density lipoprotein (VLDL) secretion. Additionally, we also found that a caveolin-1 deficiency is associated with an increase in high-density lipoprotein (HDL), and these HDL particles are enriched in cholesteryl ester in Cav-1−/− mice when compared with HDL obtained from wild-type mice. Finally, our data suggest that a caveolin-1 deficiency prevents the transcytosis of LDL across endothelial cells, and therefore, that caveolin-1 may be implicated in the regulation of plasma LDL levels. Taken together, our studies suggest that caveolin-1 plays an important role in the regulation of lipoprotein metabolism by controlling their plasma levels as well as their lipid composition. Thus caveolin-1 may also play an important role in the development of atherosclerosis

Caveolin-1 and regulation of cellular cholesterol homeostasis

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Endothelial caveolin-1 plays a major role in the development of atherosclerosis.

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Caveolin-1 regulates the anti-atherogenic properties of macrophages.

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