Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to transform into a wound-healing stroma, providing the necessary energy-rich micro-environment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship. We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energy-rich metabolites. This alternative model is still consistent with Warburg's original observation that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts (caveolin-1 (Cav-1) deficient stromal cells), shows the upregulation of both (1) myo-fibroblast markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1. Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.

Caveolae organelles and caveolin-1 protein expression are most abundant in adipocytes and endothelial cells. Our initial report on mice lacking caveolin-1 (Cav-1) demonstrated a loss of caveolae and perturbations in endothelial cell function. More recently, however, observation of the Cav-1-deficient cohorts into old age revealed significantly lower body weights, as compared with wild-type controls. These results suggest that Cav-1 null mice may have problems with lipid metabolism and/or adipocyte functioning. To test this hypothesis directly, we placed a cohort of wild-type and Cav-1 null mice on a high fat diet. Interestingly, despite being hyperphagic, Cav-1 null mice show overt resistance to diet-induced obesity. As predicted, adipocytes from Cav-1 null null mice lack caveolae membranes. Early on, a lack of caveolin-1 selectively affects only the female mammary gland fat pad and results in a near complete ablation of the hypo-dermal fat layer. There are also indications of generalized adipose tissue pathology. With increasing age, a systemic decompensation in lipid accumulation occurs resulting in dramatically smaller fat pads, histologically reduced adipocyte cell diameter, and a poorly differentiated/hypercellular white adipose parenchyma. To gain mechanistic insights into this phenotype, we show that, although serum insulin, glucose, and cholesterol levels are entirely normal, Cav-1 null mice have severely elevated triglyceride and free fatty acid levels, especially in the postprandial state. However, this build-up of triglyceriderich chylomicrons/very low density lipoproteins is not due to perturbed lipoprotein lipase activity, a major culprit of isolated hypertriglyceridemia. The lean body phenotype and metabolic defects observed in Cav-1 null mice are consistent with the previously proposed functions of caveolin-1 and caveolae in adipocytes. Our results show for the first time a clear role for caveolins in systemic lipid homeostasis in vivo and place caveolin-1/ caveolae as major factors in hyperlipidemias and obesity.

Abstract-Caveolae are 50-to 100-nm cell-surface plasma membrane invaginations observed in terminally differentiated cells. They are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking and signal transduction. The use of caveolin-1-deficient mice has provided many new insights into the roles of caveolae and caveolin-1 in the regulation of endothelial cell function. These novel findings suggest an important role for caveolin-1 in the pathogenesis of cancer, atherosclerosis, and vascular disease.

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Breast cancer is the most commonly occurring cancer in women in Western societies. 1 It is estimated that 207,090 new cases will be diagnosed and that in the United States, 39,840 women will die of the disease in 2010 (American Cancer Society, Cancer Facts & Figures 2010, http://www. cancer.org/Research/cancer-facts-and-figures-2010, last accessed November 15, 2010. Interestingly, the incidence is about 5 times higher in Western countries than in developing countries. 2 Moreover, relocation and migrational studies have demonstrated that migration from a region with low incidence to a region with high incidence increases breast cancer incidence in the immigrant population. 3 These observations suggest a strong environmental influence on breast cancer development.Diet and obesity are now considered important risk factors for cancer development. 4,5 However, despite major modifications of its metabolism during obesity development and its function in tissue pathogenesis, little is known about the metabolism and role of plasma cholesterol in cancer development. Epidemiological studies have demonstrated that patients with cancer have abnormal levels of high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol, 6,7 which are the major lipoprotein carriers of cholesterol in human plasma. In addition, numerous studies have established that transformed cells and tumors exhibit abnormal regulation of several genes that are under the control of cholesterol. The products of these genes include the LDL receptor (LDL-R), hydroxy-methyl-glutaryl coenzyme A reductase (HMG-CoA Reductase), and their regulators, the sterol regulatory element binding proteins. 8 -13 As a consequence, these genes are dysregulated at the transcriptional level during tumorigenesis. These data suggest that transformed cells may require or utilize more cholesterol than normal cells, and this may be associated with their increased rate of proliferation. More recent studies have implicated HDL during tumor formation in breast cancer. 14 -16 However, their precise function remains controversial. The present study was performed to test the hypothesis that dietary cholesterol and plasma cholesterol levels have an important role in the regulation of breast cancer onset and progression.