title: Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue.
abstract: We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the "reverse Warburg effect," because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TO MM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the "reverse Warburg effect," our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TO MM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally "fuels" tumor progression and metastatic dissemination, by "feeding" mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TO MM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA. federica.sotgia@jefferson.edu
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D027501:Monocarboxylic Acid Transporters / Q000276:immunology / Q000378:metabolism; D009124:Muscle Proteins / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress; D011956:Receptors, Cell Surface; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D011956:Receptors, Cell Surface; C406962:SLC16A4 protein, human; C084008:TOMM20 protein, human; D003576:Electron Transport Complex IV