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PMID: 20861672 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell cycle (Georgetown, Tex.) ·Vol. 9 ·No. 17 ·2010-09-01 ·Pages 3485-505

Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP

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.

MeSH Terms
3-Hydroxybutyric Acid/metabolism Animals Arginine/analogs & derivatives,metabolism Autophagy Biomarkers/analysis,blood Breast Neoplasms/diagnosis,metabolism Caveolin 1/genetics,metabolism Female Gene Expression Profiling Humans Mice MicroRNAs/metabolism Models, Biological Oxidative Stress Stromal Cells/metabolism
Chemicals
Biomarkers Caveolin 1 MIRN34a microRNA, mouse MicroRNAs Mirn31 microRNA, mouse N,N-dimethylarginine Arginine 3-Hydroxybutyric Acid
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Pavlides Stephanos
Department of Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Tsirigos Aristotelis
Migneco Gemma
Whitaker-Menezes Diana
Chiavarina Barbara
Flomenberg Neal
Frank Philippe G
Casimiro Mathew C
Wang Chenguang
Pestell Richard G
Martinez-Outschoorn Ubaldo E
Howell Anthony
Sotgia Federica
Lisanti Michael P
References (78)
78 references, click to expand
  1. Lactic acidosis and mitochondrial myopathy associated with deficiency of several components of complex III of the respiratory chain.
    Pediatr Res. 1984 Oct;18(10):991-9 PMID: 6093035
  2. The guardian's little helper: microRNAs in the p53 tumor suppressor network.
    Cancer Res. 2007 Dec 1;67(23):11099-101 PMID: 18056431
  3. Stromal gene expression predicts clinical outcome in breast cancer.
    Nat Med. 2008 May;14(5):518-27 PMID: 18438415
  4. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.
    Cell Cycle. 2009 Dec;8(23):3984-4001 PMID: 19923890
  5. Putting tumours in context.
    Nat Rev Cancer. 2001 Oct;1(1):46-54 PMID: 11900251
  6. Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis.
    Hum Pathol. 2009 Jan;40(1):83-91 PMID: 18789482
  7. dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts.
    Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H1968-74 PMID: 12384475
  8. Breast cancer by proxy: can the microenvironment be both the cause and consequence?
    Trends Mol Med. 2009 Jan;15(1):5-13 PMID: 19091631
  9. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.
    Cell Cycle. 2010 Aug 15;9(16):3256-76 PMID: 20814239
  10. Defective intramitochondrial NADH oxidation in skin fibroblasts from an infant with fatal neonatal lacticacidemia.
    Am J Hum Genet. 1985 Sep;37(5):938-46 PMID: 4050791
  11. The effect of an acute fast on human head and neck carcinoma xenograft. Growth effects on an 'isolated tumor vascular pedicle' in the nude rat.
    Arch Otolaryngol Head Neck Surg. 1993 Aug;119(8):897-902 PMID: 8343253
  12. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.
    Mol Cell Biol. 2009 May;29(10):2570-81 PMID: 19273585
  13. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model.
    Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11159-64 PMID: 15263088
  14. The anti-apoptotic action of 5-hydroxyindole: protection of mitochondrial integrity.
    Biol Pharm Bull. 2010;33(4):550-5 PMID: 20410584
  15. The efficacy and selectivity of tumor cell killing by Akt inhibitors are substantially increased by chloroquine.
    Bioorg Med Chem. 2008 Sep 1;16(17):7888-93 PMID: 18691894
  16. Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers.
    Cancer Biol Ther. 2010 Jul 15;10(2):135-43 PMID: 20431349
  17. Stromal cell expression of caveolin-1 predicts outcome in breast cancer.
    Am J Pathol. 2009 Jun;174(6):2035-43 PMID: 19411449
  18. Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine.
    Rheumatology (Oxford). 2006 Jun;45(6):676-84 PMID: 16399843
  19. Ketone bodies, potential therapeutic uses.
    IUBMB Life. 2001 Apr;51(4):241-7 PMID: 11569918
  20. A genomic screen for yeast mutants defective in mitophagy.
    Autophagy. 2010 Feb;6(2):278-80 PMID: 20364111
  21. Caveolin-1-/- null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts.
    Am J Pathol. 2009 Mar;174(3):746-61 PMID: 19234134
  22. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes.
    Mol Med. 2010 Jul-Aug;16(7-8):235-46 PMID: 20386866
  23. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
    N Engl J Med. 1986 Dec 25;315(26):1650-9 PMID: 3537791
  24. Glutathione participates in the regulation of mitophagy in yeast.
    J Biol Chem. 2009 May 29;284(22):14828-37 PMID: 19366696
  25. The paradox of autophagy and its implication in cancer etiology and therapy.
    Apoptosis. 2009 Apr;14(4):376-91 PMID: 19172397
  26. Cellular ADMA: regulation and action.
    Pharmacol Res. 2009 Dec;60(6):448-60 PMID: 19682580
  27. Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer.
    Transl Oncol. 2010 Apr;3(2):109-13 PMID: 20360935
  28. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells.
    Cancer Res. 2008 Jun 1;68(11):4331-9 PMID: 18519693
  29. Cathepsin B facilitates autophagy-mediated apoptosis in SPARC overexpressed primitive neuroectodermal tumor cells.
    Cell Death Differ. 2010 Oct;17(10):1529-39 PMID: 20339379
  30. The differentiation and function of myofibroblasts is regulated by mast cell mediators.
    J Invest Dermatol. 2001 Nov;117(5):1113-9 PMID: 11710921
  31. STUDIES ON THE TREATMENT OF MALIGNANT TUMORS WITH FIBROBLAST-INHIBITING AGENT. II. EFFECTS OF CHLOROQUINE ON ANIMAL TUMORS.
    Acta Med Okayama. 1963;17:239-52 PMID: 14164121
  32. p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication.
    Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5375-80 PMID: 20212154
  33. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
    Cancer Biol Ther. 2008 Aug;7(8):1212-25 PMID: 18458534
  34. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling.
    Cell Cycle. 2010 Jun 15;9(12):2412-22 PMID: 20562527
  35. STUDIES ON THE TREATMENT OF MALIGNANT TUMORS WITH FIBROBLAST-INHIBITING AGENT. IV. EFFECTS OF CHLOROQUINE ON MALIGNANT LYMPHOMAS.
    Acta Med Okayama. 1964 Apr;18:87-92 PMID: 14204462
  36. Neuroprotection in diet-induced ketotic rat brain after focal ischemia.
    J Cereb Blood Flow Metab. 2008 Dec;28(12):1907-16 PMID: 18648382
  37. Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms.
    Biochim Biophys Acta. 2009 Apr;1792(4):341-52 PMID: 19419692
  38. Stromal CD10 and SPARC expression in ductal carcinoma in situ (DCIS) patients predicts disease recurrence.
    Cancer Biol Ther. 2010 Aug 15;10(4):391-6 PMID: 20574156
  39. Hypoxia-induced autophagy: cell death or cell survival?
    Curr Opin Cell Biol. 2010 Apr;22(2):177-80 PMID: 20022734
  40. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.
    Am J Pathol. 2009 Jun;174(6):2023-34 PMID: 19411448
  41. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.
    Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):309-19 PMID: 14769489
  42. Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension.
    Rheumatology (Oxford). 2008 Nov;47(11):1682-5 PMID: 18753191
  43. Expression of the alpha-fetoprotein gene in human breast cancer.
    Tumour Biol. 1996;17(5):299-305 PMID: 8792856
  44. MicroRNA-210: a unique and pleiotropic hypoxamir.
    Cell Cycle. 2010 Mar 15;9(6):1072-83 PMID: 20237418
  45. Ketoacids? Good medicine?
    Trans Am Clin Climatol Assoc. 2003;114:149-61; discussion 162-3 PMID: 12813917
  46. STUDIES ON THE TREATMENT OF MALIGNANT TUMORS WITH FIBROBLAST-INHIBITING AGENT. 3. EFFECTS OF CHLOROQUINE ON HUMAN CANCERS.
    Acta Med Okayama. 1964 Apr;18:71-85 PMID: 14204461
  47. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  48. Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: role of mitochondrial dysfunction.
    Am J Physiol Cell Physiol. 2008 Jun;294(6):C1407-18 PMID: 18385287
  49. HIF-dependent antitumorigenic effect of antioxidants in vivo.
    Cancer Cell. 2007 Sep;12(3):230-8 PMID: 17785204
  50. Systemic sclerosis and cancer.
    Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):573-8 PMID: 19822074
  51. Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation.
    Cell Cycle. 2010 Jun 1;9(11):2201-19 PMID: 20519932
  52. Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus.
    Diab Vasc Dis Res. 2010 Apr;7(2):105-18 PMID: 20382774
  53. 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".
    Aging (Albany NY). 2010 Apr;2(4):185-99 PMID: 20442453
  54. Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer.
    Cancer Biol Ther. 2009 Jun;8(11):1071-9 PMID: 19502809
  55. Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer.
    Dis Markers. 2009;26(1):27-34 PMID: 19242066
  56. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation.
    Cell Cycle. 2009 Aug;8(15):2420-4 PMID: 19556867
  57. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.
    J Biol Chem. 2001 Oct 12;276(41):38121-38 PMID: 11457855
  58. miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma.
    Cancer Res. 2010 Feb 15;70(4):1635-44 PMID: 20145132
  59. Role of asymmetric-dimethyl-L-arginine (ADMA) and nitrite/nitrate (NOx) in the pathogenesis of oxidative stress in female subjects with uncomplicated type 1 diabetes mellitus.
    Diabetes Res Clin Pract. 2009 Dec;86(3):173-6 PMID: 19836094
  60. Increase of microRNA miR-31 level in plasma could be a potential marker of oral cancer.
    Oral Dis. 2010 May;16(4):360-4 PMID: 20233326
  61. Analysis of the adult human plasma metabolome.
    Pharmacogenomics. 2008 Apr;9(4):383-97 PMID: 18384253
  62. Stimulation of tumor growth in adult rats in vivo during acute streptozotocin-induced diabetes.
    Cancer Res. 1987 Apr 1;47(7):1756-61 PMID: 3815372
  63. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene.
    Brain Res. 2007 Sep 5;1167:112-7 PMID: 17689501
  64. Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium.
    Autophagy. 2008 May;4(4):527-30 PMID: 18367867
  65. A genomic screen for yeast mutants defective in selective mitochondria autophagy.
    Mol Biol Cell. 2009 Nov;20(22):4730-8 PMID: 19793921
  66. Mitochondrial membrane cholesterol, the voltage dependent anion channel (VDAC), and the Warburg effect.
    J Bioenerg Biomembr. 2008 Jun;40(3):193-7 PMID: 18677555
  67. The organizing principle: microenvironmental influences in the normal and malignant breast.
    Differentiation. 2002 Dec;70(9-10):537-46 PMID: 12492495
  68. Increased protein arginine methylation in chronic hypoxia: role of protein arginine methyltransferases.
    Am J Respir Cell Mol Biol. 2006 Oct;35(4):436-43 PMID: 16690984
  69. Epidemiological aspects of neoplasms in diabetes.
    Acta Diabetol. 2010 Jun;47(2):87-95 PMID: 20376506
  70. STUDIES ON THE TREATMENT OF MALIGNANT TUMORS WITH FIBROBLAST-INHIBITING AGENT. I. FIBROBLAST-INHIBITING ACTION OF CHLOROQUINE.
    Acta Med Okayama. 1963;17:231-8 PMID: 14165348
  71. Asymmetric dimethylarginine in hematological malignancies: a preliminary study.
    Leuk Lymphoma. 2008 Dec;49(12):2316-20 PMID: 19052979
  72. Statistical significance for genomewide studies.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5 PMID: 12883005
  73. Quis custodiet ipsos custodies: who watches the watchmen?
    Am J Pathol. 2009 Jun;174(6):1996-9 PMID: 19465642
  74. Metabolomic analysis of serum by (1) H NMR spectroscopy in amyotrophic lateral sclerosis.
    Clin Chim Acta. 2010 Apr 2;411(7-8):563-7 PMID: 20096678
  75. Towards a new "stromal-based" classification system for human breast cancer prognosis and therapy.
    Cell Cycle. 2009 Jun 1;8(11):1654-8 PMID: 19448435
  76. Metabolon, Inc.
    Pharmacogenomics. 2007 Jul;8(7):863-6 PMID: 17638516
  77. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors.
    Cell Cycle. 2010 Jun 15;9(12):2423-33 PMID: 20562526
  78. Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis.
    J Immunol. 1997 Mar 1;158(5):2310-7 PMID: 9036979
Article Info
Journal
Cell cycle (Georgetown, Tex.)
Abbr.
Cell Cycle
ISSN
1551-4005
DOI
10.4161/cc.9.17.12721
Published
2010-09-01
Pages
3485-505
Language
English
Region
United States
NLM ID
101137841
PMCID
PMC3047615
Subset
IM
Grants
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · R01 CA098779 · United States
NCI NIH HHS · R01-CA-120876 · United States
NCI NIH HHS · R01 CA120876 · United States
NCI NIH HHS · R01-CA-70896 · United States
NCI NIH HHS · R01-CA-098779 · United States
NCI NIH HHS · R01-CA-86072 · United States
NIAMS NIH HHS · R01-AR-055660 · United States
NCI NIH HHS · R01-CA-080250 · United States
NCI NIH HHS · R01 CA070896 · United States
NCI NIH HHS · R01 CA107382 · United States
NCI NIH HHS · P30 CA056036 · United States
NCI NIH HHS · P30-CA-56036 · United States
NCI NIH HHS · R01-CA-107382 · United States
NIAMS NIH HHS · R01 AR055660 · United States
NCI NIH HHS · R01-CA-75503 · United States
NCI NIH HHS · R01 CA080250 · United States
NCI NIH HHS · R01 CA086072 · United States
External Links
PubMed source DOI: 10.4161/cc.9.17.12721 PMC Full Text View journal details
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