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Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production

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Pages 2285-2302 | Published online: 15 Jun 2012

References

  • Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 2012; 7:423 - 67; http://dx.doi.org/10.1146/annurev-pathol-011811-120856; PMID: 22077552
  • Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Power surge: supporting cells “fuel” cancer cell mitochondria. Cell Metab 2012; 15:4 - 5; http://dx.doi.org/10.1016/j.cmet.2011.12.011; PMID: 22225869
  • Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, et al. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs “fertilizer”. Cell Cycle 2011; 10:2440 - 9; http://dx.doi.org/10.4161/cc.10.15.16870; PMID: 21734470
  • Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, et al. Accelerated aging in the tumor microenvironment: connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle 2011; 10:2059 - 63; http://dx.doi.org/10.4161/cc.10.13.16233; PMID: 21654190
  • Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. 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; 9:3256 - 76; http://dx.doi.org/10.4161/cc.9.16.12553; PMID: 20814239
  • Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, et al. Autophagy in cancer-associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 2010; 9:3515 - 33; http://dx.doi.org/10.4161/cc.9.17.12928; PMID: 20855962
  • Martinez-Outschoorn UE, Pestell RG, Howell A, Tykocinski ML, Nagajyothi F, Machado FS, et al. Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle 2011; 10:4208 - 16; http://dx.doi.org/10.4161/cc.10.24.18487; PMID: 22033146
  • Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 2011; 13:213; http://dx.doi.org/10.1186/bcr2892; PMID: 21867571
  • Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 2011; 10:4047 - 64; http://dx.doi.org/10.4161/cc.10.23.18151; PMID: 22134189
  • Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, et al. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle 2012; 11:1445 - 54; http://dx.doi.org/10.4161/cc.19841; PMID: 22395432
  • Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, et al. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 2010; 9:3485 - 505; http://dx.doi.org/10.4161/cc.9.17.12721; PMID: 20861672
  • Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, et al. The autophagic tumor stroma model of cancer or “battery-operated tumor growth”: A simple solution to the autophagy paradox. Cell Cycle 2010; 9:4297 - 306; http://dx.doi.org/10.4161/cc.9.21.13817; PMID: 21051947
  • Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, et al. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol 2011; 43:1045 - 51; http://dx.doi.org/10.1016/j.biocel.2011.01.023; PMID: 21300172
  • Ertel A, Tsirigos A, Whitaker-Menezes D, Birbe RC, Pavlides S, Martinez-Outschoorn UE, et al. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle 2012; 11:253 - 63; http://dx.doi.org/10.4161/cc.11.2.19006; PMID: 22234241
  • Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, et al. Towards a new “stromal-based” classification system for human breast cancer prognosis and therapy. Cell Cycle 2009; 8:1654 - 8; http://dx.doi.org/10.4161/cc.8.11.8544; PMID: 19448435
  • Witkiewicz AK, Dasgupta A, Nguyen KH, Liu C, Kovatich AJ, Schwartz GF, et al. Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer. Cancer Biol Ther 2009; 8:1071 - 9; http://dx.doi.org/10.4161/cbt.8.11.8874; PMID: 19502809
  • Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, et al. Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther 2010; 10:135 - 43; http://dx.doi.org/10.4161/cbt.10.2.11983; PMID: 20431349
  • Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 2009; 174:2023 - 34; http://dx.doi.org/10.2353/ajpath.2009.080873; PMID: 19411448
  • Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, et al. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle 2011; 10:1794 - 809; http://dx.doi.org/10.4161/cc.10.11.15675; PMID: 21521946
  • Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, et al. Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle 2012; 11:1108 - 17; http://dx.doi.org/10.4161/cc.11.6.19530; PMID: 22313602
  • Di Vizio D, Morello M, Sotgia F, Pestell RG, Freeman MR, Lisanti MP. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle 2009; 8:2420 - 4; http://dx.doi.org/10.4161/cc.8.15.9116; PMID: 19556867
  • Wu KN, Queenan M, Brody JR, Potoczek M, Sotgia F, Lisanti MP, et al. Loss of stromal caveolin-1 expression in malignant melanoma metastases predicts poor survival. Cell Cycle 2011; 10:4250 - 5; http://dx.doi.org/10.4161/cc.10.24.18551; PMID: 22134245
  • Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, et al. HIF1-alpha functions as a tumor promoter in cancer-associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle 2010; 9:3534 - 51; http://dx.doi.org/10.4161/cc.9.17.12908; PMID: 20864819
  • Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 2001; 98:12072 - 7; http://dx.doi.org/10.1073/pnas.211053698; PMID: 11593017
  • Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol 2002; 34:1401 - 14; http://dx.doi.org/10.1016/S1357-2725(02)00053-5; PMID: 12200035
  • Coppé JP, Rodier F, Patil CK, Freund A, Desprez PY, Campisi J. Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 2011; 286:36396 - 403; http://dx.doi.org/10.1074/jbc.M111.257071; PMID: 21880712
  • Young AR, Narita M. Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol 2010; 22:234 - 40; http://dx.doi.org/10.1016/j.ceb.2009.12.005; PMID: 20045302
  • Narita M, Young AR, Narita M. Autophagy facilitates oncogene-induced senescence. Autophagy 2009; 5:1046 - 7; http://dx.doi.org/10.4161/auto.5.7.9444; PMID: 19652542
  • Tian LM, Xie HF, Xiao X, Yang T, Hu YH, Wang WZ, et al. Study on the roles of β-catenin in hydrogen peroxide-induced senescence in human skin fibroblasts. Exp Dermatol 2011; 20:836 - 8; http://dx.doi.org/10.1111/j.1600-0625.2011.01324.x; PMID: 21707762
  • Liu DH, Chen YM, Liu Y, Hao BS, Zhou B, Wu L, et al. Rb1 protects endothelial cells from hydrogen peroxide-induced cell senescence by modulating redox status. Biol Pharm Bull 2011; 34:1072 - 7; http://dx.doi.org/10.1248/bpb.34.1072; PMID: 21720015
  • Waghray M, Cui Z, Horowitz JC, Subramanian IM, Martinez FJ, Toews GB, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 2005; 19:854 - 6; PMID: 15857893
  • Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 2000; 113:3613 - 22; PMID: 11017877
  • Gerland LM, Peyrol S, Lallemand C, Branche R, Magaud JP, Ffrench M. Association of increased autophagic inclusions labeled for beta-galactosidase with fibroblastic aging. Exp Gerontol 2003; 38:887 - 95; http://dx.doi.org/10.1016/S0531-5565(03)00132-3; PMID: 12915210
  • Robbins E, Levine EM, Eagle H. Morphologic changes accompanying senescence of cultured human diploid cells. J Exp Med 1970; 131:1211 - 22; http://dx.doi.org/10.1084/jem.131.6.1211; PMID: 5419270
  • Stöckl P, Hütter E, Zwerschke W, Jansen-Dürr P. Sustained inhibition of oxidative phosphorylation impairs cell proliferation and induces premature senescence in human fibroblasts. Exp Gerontol 2006; 41:674 - 82; http://dx.doi.org/10.1016/j.exger.2006.04.009; PMID: 16713693
  • Goldstein S, Ballantyne SR, Robson AL, Moerman EJ. Energy metabolism in cultured human fibroblasts during aging in vitro. J Cell Physiol 1982; 112:419 - 24; http://dx.doi.org/10.1002/jcp.1041120316; PMID: 6127343
  • Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 2006; 5:187 - 95; http://dx.doi.org/10.1111/j.1474-9726.2006.00199.x; PMID: 16626397
  • White E, Lowe SW. Eating to exit: autophagy-enabled senescence revealed. Genes Dev 2009; 23:784 - 7; http://dx.doi.org/10.1101/gad.1795309; PMID: 19339684
  • Chen J, Goligorsky MS. Premature senescence of endothelial cells: Methusaleh’s dilemma. Am J Physiol Heart Circ Physiol 2006; 290:H1729 - 39; http://dx.doi.org/10.1152/ajpheart.01103.2005; PMID: 16603702
  • Sasaki M, Ikeda H, Yamaguchi J, Miyakoshi M, Sato Y, Nakanuma Y. Bile ductular cells undergoing cellular senescence increase in chronic liver diseases along with fibrous progression. Am J Clin Pathol 2010; 133:212 - 23; http://dx.doi.org/10.1309/AJCPWMX47TREYWZG; PMID: 20093230
  • Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab Invest 2010; 90:835 - 43; http://dx.doi.org/10.1038/labinvest.2010.56; PMID: 20212459
  • Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010; 53:318 - 25; http://dx.doi.org/10.1016/j.jhep.2010.03.008; PMID: 20570384
  • Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Autophagy may precede cellular senescence of bile ductular cells in ductular reaction in primary biliary cirrhosis. Dig Dis Sci 2012; 57:660 - 6; http://dx.doi.org/10.1007/s10620-011-1929-y; PMID: 21989821
  • Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis. Liver Int 2012; 32:487 - 99; PMID: 22098537
  • Chatzistamou I, Dioufa N, Trimis G, Sklavounou A, Kittas C, Kiaris H, et al. p21/waf1 and smooth-muscle actin α expression in stromal fibroblasts of oral cancers. Cell Oncol (Dordr) 2011; 34:483 - 8; http://dx.doi.org/10.1007/s13402-011-0044-6; PMID: 21559927
  • Luo Y, Zou P, Zou J, Wang J, Zhou D, Liu L. Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKα dependent manner. Exp Gerontol 2011; 46:860 - 7; http://dx.doi.org/10.1016/j.exger.2011.07.005; PMID: 21816217
  • Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging (Albany NY) 2009; 1:1008 - 16; PMID: 20157583
  • Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 2008; 14:518 - 27; http://dx.doi.org/10.1038/nm1764; PMID: 18438415
  • Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, et al. 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; 2:185 - 99; PMID: 20442453
  • Chinnadurai G, Vijayalingam S, Gibson SB. BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 2008; 27:Suppl 1 S114 - 27; http://dx.doi.org/10.1038/onc.2009.49; PMID: 19641497
  • Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, et al. 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; 9:2423 - 33; http://dx.doi.org/10.4161/cc.9.12.12048; PMID: 20562526
  • Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 2009; 29:2570 - 81; http://dx.doi.org/10.1128/MCB.00166-09; PMID: 19273585
  • Mazure NM, Pouysségur J. Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009; 5:868 - 9; PMID: 19587545
  • Ha SD, Ham B, Mogridge J, Saftig P, Lin S, Kim SO. Cathepsin B-mediated autophagy flux facilitates the anthrax toxin receptor 2-mediated delivery of anthrax lethal factor into the cytoplasm. J Biol Chem 2010; 285:2120 - 9; http://dx.doi.org/10.1074/jbc.M109.065813; PMID: 19858192
  • Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 2003; 116:1679 - 88; http://dx.doi.org/10.1242/jcs.00381; PMID: 12665549
  • Ravikumar B, Moreau K, Rubinsztein DC. Plasma membrane helps autophagosomes grow. Autophagy 2010; 6:1184 - 6; http://dx.doi.org/10.4161/auto.6.8.13428; PMID: 20861674
  • Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 2010; 12:747 - 57; http://dx.doi.org/10.1038/ncb2078; PMID: 20639872
  • Goldman SJ, Taylor R, Zhang Y, Jin S. Autophagy and the degradation of mitochondria. Mitochondrion 2010; 10:309 - 15; http://dx.doi.org/10.1016/j.mito.2010.01.005; PMID: 20083234
  • Yamashita M, Ogawa T, Zhang X, Hanamura N, Kashikura Y, Takamura M, et al. Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. Breast Cancer 2012; 19:170 - 6; http://dx.doi.org/10.1007/s12282-010-0234-5; PMID: 20978953
  • Nomura H, Uzawa K, Yamano Y, Fushimi K, Ishigami T, Kouzu Y, et al. 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; 40:83 - 91; http://dx.doi.org/10.1016/j.humpath.2008.06.018; PMID: 18789482
  • Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23:798 - 803; http://dx.doi.org/10.1101/gad.519709; PMID: 19279323
  • Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 2011; 332:966 - 70; http://dx.doi.org/10.1126/science.1205407; PMID: 21512002
  • Zoncu R, Sabatini DM. Cell biology. The TASCC of secretion. Science 2011; 332:923 - 5; http://dx.doi.org/10.1126/science.1207552; PMID: 21596981
  • Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999; 59:59 - 65; http://dx.doi.org/10.1006/geno.1999.5851; PMID: 10395800
  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402:672 - 6; http://dx.doi.org/10.1038/45257; PMID: 10604474
  • Mariño G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, López-Otín C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 2007; 282:18573 - 83; http://dx.doi.org/10.1074/jbc.M701194200; PMID: 17442669
  • Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 2007; 17:422 - 7; http://dx.doi.org/10.1016/j.tcb.2007.07.009; PMID: 17804237
  • Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009; 16:87 - 93; http://dx.doi.org/10.1038/cdd.2008.131; PMID: 18806760
  • Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17:1498 - 503; http://dx.doi.org/10.1038/nm.2492; PMID: 22037646
  • Martinez-Outschoorn UE, Lin Z, Trimmer C, Flomenberg N, Wang C, Pavlides S, et al. Cancer cells metabolically “fertilize” the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle 2011; 10:2504 - 20; http://dx.doi.org/10.4161/cc.10.15.16585; PMID: 21778829
  • Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, et al. 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; 9:2201 - 19; http://dx.doi.org/10.4161/cc.9.11.11848; PMID: 20519932
  • Pavlides S, Vera I, Gandara R, Sneddon S, Pestell RG, Mercier I, et al. Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and Metastasis via Oxidative Stress, Mitophagy, and Aerobic Glycolysis. Antioxid Redox Signal 2011; PMID: 21883043
  • Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8:3984 - 4001; http://dx.doi.org/10.4161/cc.8.23.10238; PMID: 19923890
  • Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010; 9:3506 - 14; http://dx.doi.org/10.4161/cc.9.17.12731; PMID: 20818174
  • Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, et al. Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle 2011; 10:1271 - 86; http://dx.doi.org/10.4161/cc.10.8.15330; PMID: 21512313
  • Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, et al. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 2011; 10:1772 - 83; http://dx.doi.org/10.4161/cc.10.11.15659; PMID: 21558814
  • Cahill GF Jr., Veech RL. Ketoacids? Good medicine?. Trans Am Clin Climatol Assoc 2003; 114:149 - 61, discussion 162-3; PMID: 12813917
  • Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr.. Ketone bodies, potential therapeutic uses. IUBMB Life 2001; 51:241 - 7; http://dx.doi.org/10.1080/152165401753311780; PMID: 11569918
  • McPherson PA, McEneny J. The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem 2012; 68:141 - 51; http://dx.doi.org/10.1007/s13105-011-0112-4; PMID: 21983804
  • Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE. The impact of diabetes on survival following breast cancer. Breast Cancer Res Treat 2008; 109:389 - 95; http://dx.doi.org/10.1007/s10549-007-9654-0; PMID: 17659440
  • Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 2008; 300:2754 - 64; http://dx.doi.org/10.1001/jama.2008.824; PMID: 19088353
  • Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 2000; 59:271 - 8; http://dx.doi.org/10.1023/A:1006308619659; PMID: 10832597
  • Chen J, Xavier S, Moskowitz-Kassai E, Chen R, Lu CY, Sanduski K, et al. Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress-induced premature senescence. Am J Pathol 2012; 180:973 - 83; http://dx.doi.org/10.1016/j.ajpath.2011.11.033; PMID: 22234173
  • Blagosklonny MV, Campisi J, Sinclair DA. Aging: past, present and future. Aging (Albany NY) 2009; 1:1 - 5; PMID: 20157590