title: The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.
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.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephanos
authors.initials: S
authors.lastname: Pavlides
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.forename: Gemma
authors.initials: G
authors.lastname: Migneco
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiavarina
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001343:Autophagy; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051242:Caveolin 1; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; C018524:N,N-dimethylarginine; D001120:Arginine; D020155:3-Hydroxybutyric Acid