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    The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.

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    Authors
    Pavlides, S
    Tsirigos, A
    Migneco, G
    Whitaker-Menezes, D
    Chiavarina, B
    Flomenberg, N
    Frank, P G
    Casimiro, M C
    Wang, C
    Pestell, R G
    Martinez-Outschoorn, U E
    Howell, Anthony
    Sotgia, Federica
    Lisanti, Michael P
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    Affiliation
    Department of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
    Issue Date
    2010-09
    
    Metadata
    Show full item record
    Abstract
    A loss of stromal Cav-1 in the tumor fibroblast compartment is associated with early tumor recurrence, lymph-node metastasis, and tamoxifen-resistance, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this "lethal tumor micro-environment." Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav-1 (-/-) stromal cells revealed the upregulation of two key cancer-related miR's, namely miR-31 and miR-34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress (miR-34c) or activation of the hypoxic response/HIF1a (miR-31), which is sufficient to drive authophagy/mitophagy. Thus, via an unbiased comprehensive analysis of a lethal tumor micro-environment, we have identified a number of candidate biomarkers (ADMA, ketones, and miR-31/34c) that could be used to identify high-risk cancer patients at diagnosis, for treatment stratification and/or for evaluating therapeutic efficacy during anti-cancer therapy. We propose that the levels of these key biomarkers (ADMA, ketones/BHB, miR-31, and miR-34c) could be (1) assayed using serum or plasma from cancer patients, or (2) performed directly on excised tumor tissue. Importantly, induction of oxidative stress and autophagy/mitophagy in the tumor stromal compartment provides a means by which epithelial cancer cells can directly "feed off" of stromal-derived essential nutrients, chemical building blocks (amino acids, nucleotides), and energy-rich metabolites (glutamine, pyruvate, ketones/BHB), driving tumor progression and metastasis. Essentially, aggressive cancer cells are "eating" the cancer-associated fibroblasts via autophagy/mitophagy in the tumor micro-environment. Lastly, we discuss that this "Autophagic Tumor Stroma Model of Cancer Metabolism" provides a viable solution to the "Autophagy Paradox" in cancer etiology and chemo-therapy.
    Citation
    The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. 2010, 9 (17):3485-505 Cell Cycle
    Journal
    Cell Cycle
    URI
    http://hdl.handle.net/10541/115747
    DOI
    10.4161/cc.9.17.12721
    PubMed ID
    20861672
    Type
    Article
    Language
    en
    ISSN
    1551-4005
    ae974a485f413a2113503eed53cd6c53
    10.4161/cc.9.17.12721
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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