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    Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue.

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    Authors
    Sotgia, F
    Whitaker-Menezes, D
    Martinez-Outschoorn, U
    Flomenberg, N
    Birbe, R
    Witkiewicz, A
    Howell, Anthony
    Philp, N
    Pestell, R
    Lisanti, Michael P
    Affiliation
    The Jefferson Stem Cell Biology and Regenerative Medicine Center; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA; Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA; Manchester Breast Centre & Breakthrough Breast Cancer Research Unit; Paterson Institute for Cancer Research; School of Cancer; Enabling Sciences and Technology; Manchester Academic Health Science Centre; University of Manchester; UK.
    Issue Date
    2012-04-01
    
    Metadata
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    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.
    Citation
    Mitochondrial metabolism in cancer metastasis: Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. 2012, 11 (7):1445-1454 Cell Cycle
    Journal
    Cell Cycle
    URI
    http://hdl.handle.net/10541/230516
    DOI
    10.4161/cc.19841
    PubMed ID
    22395432
    Type
    Article
    Language
    en
    ISSN
    1551-4005
    ae974a485f413a2113503eed53cd6c53
    10.4161/cc.19841
    Scopus Count
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