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"

Abstract

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-marrowderived stromal cells bear a striking resemblance to the activated tumor stroma of human breast cancers. Morespecifically, the transcriptional profiles of Cav-1 (-/-) stromal cells were most closely related to the primary tumor stroma ofbreast cancer patients that had undergone lymph-node (LN) metastasis. This is consistent with previous morphologicaldata 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 breastcancers shows a transcriptional shift towards oxidative stress, DNA damage/repair, inflammation, hypoxia, and aerobicglycolysis, consistent with the "Reverse Warburg Effect". Finally, the tumor stroma of "metastasis-prone" breast cancerpatients 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 andneuro-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, aerobicglycolysis, and inflammation, driving the "Reverse Warburg Effect" in the tumor micro-environment and cancer cellmetastasis. © Pavlides et al.