Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

Breast Cancer Research

Volumn 13, Issue 4, 2011, Pages

  Sotgia, Federica ^a,b,c   Martinez Outschoorn, Ubaldo E ^a,b,d   Pavlides, Stephanos ^a,b   Howell, Anthony ^c   Pestell, Richard G ^a,b,d   Lisanti, Michael P ^a,b,c,d  

^a Jefferson Stem Cell Biology and Regenerative Medicine Center   (United States)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

^c UNIVERSITY OF MANCHESTER   (United Kingdom)

^d THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMMONIA; ANGIOGENESIS INHIBITOR; CAVEOLIN 1; GLUTAMINE; TUMOR MARKER; CAV1 PROTEIN, HUMAN; MITOCHONDRIAL DNA;

ADVERSE OUTCOME; AEROBIC GLYCOLYSIS; AUTOPHAGY; BIOENERGY; BIOSYNTHESIS; CANCER DIAGNOSIS; CANCER GROWTH; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER RESISTANCE; CANCER THERAPY; CELL COMPARTMENTALIZATION; CELL HYPOXIA; CELL METABOLISM; CELL PROTECTION; CLINICAL OUTCOME; DIAGNOSTIC IMAGING; DISEASE ACTIVITY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENERGY RESOURCE; HOST CELL; HUMAN; MALIGNANT NEOPLASM; METASTASIS; MITOCHONDRIAL RESPIRATION; MITOPHAGY; MUTAGENESIS; NONHUMAN; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PREDICTIVE VALUE; PROTEIN DEPLETION; REVIEW; STROMA; TISSUE OXYGENATION; TUMOR MICROENVIRONMENT; BREAST TUMOR; CELL DEATH; EPITHELIUM CELL; METABOLISM; MITOCHONDRION; PATHOLOGY; PROGNOSIS; STROMA CELL;

AMMONIA; AUTOPHAGY; BREAST NEOPLASMS; CAVEOLIN 1; CELL DEATH; CELL HYPOXIA; DNA, MITOCHONDRIAL; EPITHELIAL CELLS; GLUTAMINE; HUMANS; MITOCHONDRIA; OXIDATIVE STRESS; PREDICTIVE VALUE OF TESTS; PROGNOSIS; STROMAL CELLS; TUMOR MARKERS, BIOLOGICAL; TUMOR MICROENVIRONMENT;

EID: 82855167795     PISSN: 14655411     EISSN: 1465542X     Source Type: Journal    
DOI: 10.1186/bcr2892     Document Type: Review

References (125)

1. Warburg O: On the origin of cancer cells. Science. 1956, 123: 309-314. 10.1126/science.123.3191.309.
2. Dang CV: PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect. Sci Signal. 2009, 2: pe75-10.1126/scisignal.297pe75.
3. Cairns RA, Harris IS, Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 2011, 11: 85-95. 10.1038/nrc2981.
4. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB: Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008, 18: 54-61. 10.1016/j.gde.2008.02.003.
5. Guppy M, Leedman P, Zu X, Russell V: Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002, 364: 309-315.
6. Kallinowski F, Vaupel P, Runkel S, Berg G, Fortmeyer HP, Baessler KH, Wagner K, Mueller-Klieser W, Walenta S: Glucose uptake, lactate release, ketone body turnover, metabolic micromilieu, and pH distributions in human breast cancer xenografts in nude rats. Cancer Res. 1988, 48: 7264-7272.
7. Zu XL, Guppy M: Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun. 2004, 313: 459-465. 10.1016/j.bbrc.2003.11.136.
8. Kallinowski F, Schlenger KH, Runkel S, Kloes M, Stohrer M, Okunieff P, Vaupel P: Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts. Cancer Res. 1989, 49: 3759-3764.
9. Gstraunthaler G, Seppi T, Pfaller W: Impact of culture conditions, culture media volumes, and glucose content on metabolic properties of renal epithelial cell cultures. Are renal cells in tissue culture hypoxic?. Cell Physiol Biochem. 1999, 9: 150-172. 10.1159/000016312.
10. Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E: Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res. 2006, 66: 632-637. 10.1158/0008-5472.CAN-05-3260.
11. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009, 360: 765-773. 10.1056/NEJMoa0808710.
12. Fogal V, Richardson AD, Karmali PP, Scheffler IE, Smith JW, Ruoslahti E: Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol. 2010, 30: 1303-1318. 10.1128/MCB.01101-09.
13. Sheen-Chen SM, Huang CC, Tang RP, Chou FF, Eng HL: Prognostic value of signal transducers and activators of transcription 3 in breast cancer. Cancer Epidemiol Biomarkers Prev. 2008, 17: 2286-2290. 10.1158/1055-9965.EPI-08-0089.
14. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC: Function of mitochondrial Stat3 in cellular respiration. Science. 2009, 323: 793-797. 10.1126/science.1164551.
15. Reich NC: STAT3 revs up the powerhouse. Sci Signal. 2009, 2: pe61-10.1126/scisignal.290pe61.
16. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE: Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009, 324: 1713-1716. 10.1126/science.1171721.
17. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS: Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010, 107: 8788-8793. 10.1073/pnas.1003428107.
18. Berridge MV, Tan AS: Effects of mitochondrial gene deletion on tumorigenicity of metastatic melanoma: reassessing the Warburg effect. Rejuvenation Res. 2010, 13: 139-141. 10.1089/rej.2009.0948.
19. Yu M, Shi Y, Wei X, Yang Y, Zhou Y, Hao X, Zhang N, Niu R: Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells. Toxicol Lett. 2007, 170: 83-93. 10.1016/j.toxlet.2007.02.013.
20. Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, Pestell R: Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol. 2006, 26: 5449-5469. 10.1128/MCB.02074-05.
21. Bostrom P, Soderstrom M, Palokangas T, Vahlberg T, Collan Y, Carpen O, Hirsimaki P: Analysis of cyclins A, B1, D1 and E in breast cancer in relation to tumour grade and other prognostic factors. BMC Res Notes. 2009, 2: 140-10.1186/1756-0500-2-140.
22. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV: c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009, 458: 762-765. 10.1038/nature07823.
23. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008, 105: 18782-18787. 10.1073/pnas.0810199105.
24. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA: Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010, 18: 207-219. 10.1016/j.ccr.2010.08.009.
25. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 2006, 6: 392-401. 10.1038/nrc1877.
26. Ronnov-Jessen L, Petersen OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996, 76: 69-125.
27. Shekhar MP, Pauley R, Heppner G: Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 2003, 5: 130-135. 10.1186/bcr580.
28. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005, 121: 335-348. 10.1016/j.cell.2005.02.034.
29. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007, 449: 557-563. 10.1038/nature06188.
30. Wu M, Jung L, Cooper AB, Fleet C, Chen L, Breault L, Clark K, Cai Z, Vincent S, Bottega S, Shen Q, Richardson A, Bosenburg M, Naber SP, DePinho RA, Kuperwasser C, Robinson MO: Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice. Proc Natl Acad Sci USA. 2009, 106: 7022-7027. 10.1073/pnas.0811785106.
31. Howell A, Landberg G, Bergh J: Breast tumour stroma is a prognostic indicator and target for therapy. Breast Cancer Res. 2009, 11 (Suppl 3): S16-10.1186/bcr2435.
32. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M: Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008, 14: 518-527. 10.1038/nm1764.
33. Ma XJ, Dahiya S, Richardson E, Erlander M, Sgroi DC: Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 2009, 11: R7-10.1186/bcr2222.
34. Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L, Hatzis C, Hortobagyi GN, Andre F, Gianni L, Symmans WF, Pusztai L: Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol. 2010, 28: 4316-4323. 10.1200/JCO.2009.27.2419.
35. Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, Jasmin JF, Frank PG, Pestell RG, Kleer CG, Sotgia F, Lisanti MP: Towards a new "stromal-based" classification system for human breast cancer prognosis and therapy. Cell Cycle. 2009, 8: 1654-1658. 10.4161/cc.8.11.8544.
36. Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, Fanelli MA, Cuello-Carrion FD, Gago FE, Anderson RL: Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol. 2009, 174: 2035-2043. 10.2353/ajpath.2009.080924.
37. Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, Sotgia F, Brody JR, Mitchell EP, Lisanti MP: Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther. 2010, 10: 135-143. 10.4161/cbt.10.2.11983.
38. 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: 2420-2424. 10.4161/cc.8.15.9116.
39. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez- Outschoorn UE, Sotgia F, Lisanti MP: The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009, 8: 3984-4001. 10.4161/cc.8.23.10238.
40. Bosch M, Mari M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, González-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, Garcia-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A: Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol. 2011, 21: 681-686. 10.1016/j.cub.2011.03.030.
41. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP: 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: 3256-3276. 10.4161/cc.9.16.12553.
42. Mueller-Lisse UG, Mueller-Lisse UL: Imaging of advanced renal cell carcinoma. World J Urol. 2010, 28: 253-261. 10.1007/s00345-010-0557-z.
43. Avril N, Dambha F, Murray I, Shamash J, Powles T, Sahdev A: The clinical advances of fluorine-2-D-deoxyglucose--positron emission tomography/computed tomography in urological cancers. Int J Urol. 2010, 17: 501-511. 10.1111/j.1442-2042.2010.02509.x.
44. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, et al: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994, 7: 85-90. 10.1038/ng0594-85.
45. Cowey CL, Rathmell WK: VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug effi cacy. Curr Oncol Rep. 2009, 11: 94-101. 10.1007/s11912-009-0015-5.
46. Tanimoto K, Makino Y, Pereira T, Poellinger L: Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 2000, 19: 4298-4309. 10.1093/emboj/19.16.4298.
47. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW: Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA. 2000, 97: 10430-10435.
48. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG: Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000, 2: 423-427. 10.1038/35017054.
49. Weiler-Sagie M, Bushelev O, Epelbaum R, Dann EJ, Haim N, Avivi I, Ben-Barak A, Ben-Arie Y, Bar-Shalom R, Israel O: (18)F-FDG avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med. 2010, 51: 25-30. 10.2967/jnumed.109.067892.
50. Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A: The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol. 2010, 221: 248-263. 10.1002/path.2711.
51. Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H, Kayani I, Menezes LJ, Dickson JC, Ell PJ: Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with 18FFDG PET/CT. J Nucl Med. 2009, 50: 538-545. 10.2967/jnumed.108.057901.
52. Su YQ, Sugiura K, Eppig JJ: Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin Reprod Med. 2009, 27: 32-42. 10.1055/s-0028-1108008.
53. Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, O'Brien MJ, Matzuk MM, Shimasaki S, Eppig JJ: Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development. 2007, 134: 2593-2603. 10.1242/dev.006882.
54. Biggers JD, Whittingham DG, Donahue RP: The pattern of energy metabolism in the mouse oocyte and zygote. Proc Natl Acad Sci USA. 1967, 58: 560-567. 10.1073/pnas.58.2.560.
55. Brinster RL: Studies on the development of mouse embryos in vitro. Ii. The effect of energy source. J Exp Zool. 1965, 158: 59-68. 10.1002/jez.1401580106.
56. Sugiura K, Pendola FL, Eppig JJ: Oocyte control of metabolic cooperativity between oocytes and companion granulosa cells: energy metabolism. Dev Biol. 2005, 279: 20-30. 10.1016/j.ydbio.2004.11.027.
57. Brinster RL: Oxidation of pyruvate and glucose by oocytes of the mouse and rhesus monkey. J Reprod Fertil. 1971, 24: 187-191. 10.1530/jrf.0.0240187.
58. Colonna R, Mangia F: Mechanisms of amino acid uptake in cumulusenclosed mouse oocytes. Biol Reprod. 1983, 28: 797-803. 10.1095/biolreprod28.4.797.
59. Su YQ, Sugiura K, Wigglesworth K, O'Brien MJ, Affourtit JP, Pangas SA, Matzuk MM, Eppig JJ: Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development. 2008, 135: 111-121.
60. Tsacopoulos M, Magistretti PJ: Metabolic coupling between glia and neurons. J Neurosci. 1996, 16: 877-885.
61. Magistretti PJ, Pellerin L: Cellular mechanisms of brain energy metabolism. Relevance to functional brain imaging and to neurodegenerative disorders. Ann N Y Acad Sci. 1996, 777: 380-387. 10.1111/j.1749-6632.1996.tb34449.x.
62. Bittar PG, Charnay Y, Pellerin L, Bouras C, Magistretti PJ: Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J Cereb Blood Flow Metab. 1996, 16: 1079-1089.
63. Laughton JD, Bittar P, Charnay Y, Pellerin L, Kovari E, Magistretti PJ, Bouras C: Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase. BMC Neurosci. 2007, 8: 35-10.1186/1471-2202-8-35.
64. Connett RJ, Gayeski TE, Honig CR: Lactate accumulation in fully aerobic, working, dog gracilis muscle. Am J Physiol. 1984, 246: H120-128.
65. McCullagh KJ, Poole RC, Halestrap AP, Tipton KF, O'Brien M, Bonen A: Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle. Am J Physiol. 1997, 273: E239-246.
66. Brooks GA: The lactate shuttle during exercise and recovery. Med Sci Sports Exerc. 1986, 18: 360-368. 10.1249/00005768-198606000-00019.
67. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP: 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: 1772-1783. 10.4161/cc.10.11.15659.
68. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C, Bellanger D, Stern MH, Dubois T, Sastre-Garau X, Delattre O, Vincent-Salomon A, Mechta-Grigoriou F: Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med. 2010, 2: 211-230. 10.1002/emmm.201000073.
69. Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, Migneco G, Witkiewicz AK, Martinez-Cantarin MP, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F: 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: 2423-2433. 10.4161/cc.9.12.12048.
70. Ramanathan A, Wang C, Schreiber SL: Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci USA. 2005, 102: 5992-5997. 10.1073/pnas.0502267102.
71. Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Flomenberg N, Tsirigos A, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP: Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling. Cell Cycle. 2010, 9: 2412-2422. 10.4161/cc.9.12.11989.
72. Sung SY, Hsieh CL, Law A, Zhau HE, Pathak S, Multani AS, Lim S, Coleman IM, Wu LC, Figg WD, Dahut WL, Nelson P, Lee JK, Amin MB, Lyles R, Johnstone PA, Marshall FF, Chung LW: Coevolution of prostate cancer and bone stroma in three-dimensional coculture: implications for cancer growth and metastasis. Cancer Res. 2008, 68: 9996-10003. 10.1158/0008-5472.CAN-08-2492.
73. Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F: Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther. 2010, 10: 537-542.
74. 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: The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010, 9: 3485-3505. 10.4161/cc.9.17.12721.
75. Azad MB, Gibson SB: Role of BNIP3 in proliferation and hypoxia-induced autophagy: implications for personalized cancer therapies. Ann N Y Acad Sci. 2010, 1210: 8-16. 10.1111/j.1749-6632.2010.05778.x.
76. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, Sugimoto T, Haneda M, Kashiwagi A, Koya D: Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest. 2010, 120: 1043-1055. 10.1172/JCI41376.
77. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM: Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003, 3: 347-361. 10.1016/S1535-6108(03)00085-0.
78. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F: Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle. 2010, 9: 3515-3533. 10.4161/cc.9.17.12928.
79. Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP: 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: 3534-3551. 10.4161/cc.9.17.12908.
80. Nomura H, Uzawa K, Yamano Y, Fushimi K, Ishigami T, Kouzu Y, Koike H, Siiba M, Bukawa H, Yokoe H, Kubosawa H, Tanzawa H: 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. 10.1016/j.humpath.2008.06.018.
81. Nadji M, Fresno M, Nassiri M, Conner G, Herrero A, Morales AR: Cathepsin D in host stromal cells, but not in tumor cells, is associated with aggressive behavior in node-negative breast cancer. Hum Pathol. 1996, 27: 890-895. 10.1016/S0046-8177(96)90214-2.
82. Kleer CG, Bloushtain-Qimron N, Chen YH, Carrasco D, Hu M, Yao J, Kraeft SK, Collins LC, Sabel MS, Argani P, Gelman R, Schnitt SJ, Krop IE, Polyak K: Epithelial and stromal cathepsin K and CXCL14 expression in breast tumor progression. Clin Cancer Res. 2008, 14: 5357-5367. 10.1158/1078-0432.CCR-08-0732.
83. Levine B, Kroemer G: Autophagy in the pathogenesis of disease. Cell. 2008, 132: 27-42. 10.1016/j.cell.2007.12.018.
84. Denkert C, Budczies J, Kind T, Weichert W, Tablack P, Sehouli J, Niesporek S, Konsgen D, Dietel M, Fiehn O: Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res. 2006, 66: 10795-10804. 10.1158/0008-5472.CAN-06-0755.
85. Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, Kinoshita T, Saito N, Ochiai A, Tomita M, Esumi H, Soga T: Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009, 69: 4918-4925. 10.1158/0008-5472.CAN-08-4806.
86. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009, 457: 910-914. 10.1038/nature07762.
87. Eisenberg-Lerner A, Kimchi A: The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009, 14: 376-391. 10.1007/s10495-008-0307-5.
88. Maclean KH, Dorsey FC, Cleveland JL, Kastan MB: Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 2008, 118: 79-88. 10.1172/JCI33700.
89. Sparks CA, Guertin DA: Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene. 2010, 29: 3733-3744. 10.1038/onc.2010.139.
90. Loges S, Mazzone M, Hohensinner P, Carmeliet P: Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009, 15: 167-170. 10.1016/j.ccr.2009.02.007.
91. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009, 15: 220-231. 10.1016/j.ccr.2009.01.027.
92. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009, 15: 232-239. 10.1016/j.ccr.2009.01.021.
93. Blagosklonny MV: Antiangiogenic therapy and tumor progression. Cancer Cell. 2004, 5: 13-17. 10.1016/S1535-6108(03)00336-2.
94. Tisdale MJ: Cancer cachexia. Curr Opin Gastroenterol. 2010, 26: 146-151. 10.1097/MOG.0b013e3283347e77.
95. Holmes S: A difficult clinical problem: diagnosis, impact and clinical management of cachexia in palliative care. Int J Palliat Nurs. 2009, 15: 322-326.
96. McClung JM, Judge AR, Powers SK, Yan Z: p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol. 2010, 298: C542-549. 10.1152/ajpcell.00192.2009.
97. Asp ML, Tian M, Wendel AA, Belury MA: Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int J Cancer. 2010, 126: 756-763. 10.1002/ijc.24784.
98. Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Pavlides S, Sotgia F, Lisanti MP: Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle. 2011, 10: 1794-1809. 10.4161/cc.10.11.15675.
99. Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F: Cytokine production and inflammation drive autophagy in the tumor microenvironment: Role of stromal caveolin-1 as a key regulator. Cell Cycle. 2011, 10: 1784-1793. 10.4161/cc.10.11.15674.
100. Dang CV: Glutaminolysis: supplying carbon or nitrogen or both for cancer cells?. Cell Cycle. 2010, 9: 3884-3886. 10.4161/cc.9.19.13302.
101. Wise DR, Thompson CB: Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010, 35: 427-433. 10.1016/j.tibs.2010.05.003.
102. Dang CV, Le A, Gao P: MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009, 15: 6479-6483. 10.1158/1078-0432.CCR-09-0889.
103. Kaadige MR, Looper RE, Kamalanaadhan S, Ayer DE: Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proc Natl Acad Sci USA. 2009, 106: 14878-14883. 10.1073/pnas.0901221106.
104. Eng CH, Abraham RT: Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy. 2010, 6: 968-970. 10.4161/auto.6.7.13082.
105. Eng CH, Yu K, Lucas J, White E, Abraham RT: Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal. 2010, 3: ra31-10.1126/scisignal.2000911.
106. Marino G, Kroemer G: Ammonia: a diffusible factor released by proliferating cells that induces autophagy. Sci Signal. 2010, 3: pe19-10.1126/scisignal.3124pe19.
107. Dey S, Guha M, Alam A, Goyal M, Bindu S, Pal C, Maity P, Mitra K, Bandyopadhyay U: Malarial infection develops mitochondrial pathology and mitochondrial oxidative stress to promote hepatocyte apoptosis. Free Radic Biol Med. 2009, 46: 271-281. 10.1016/j.freeradbiomed.2008.10.032.
108. Postma NS, Mommers EC, Eling WM, Zuidema J: Oxidative stress in malaria; implications for prevention and therapy. Pharm World Sci. 1996, 18: 121-129. 10.1007/BF00717727.
109. Siddiqi NJ, Alhomida AS: Status of hepatic oxidative stress and antioxidant defense systems during chloroquine treatment of Plasmodium yoelii nigeriensis infected mice. In Vivo. 1999, 13: 547-550.
110. Solomon VR, Lee H: Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol. 2009, 625: 220-233. 10.1016/j.ejphar.2009.06.063.
111. Murchison EP: Clonally transmissible cancers in dogs and Tasmanian devils. Oncogene. 2008, 27 (Suppl 2): S19-30.
112. Thomas R, Rebbeck C, Leroi AM, Burt A, Breen M: Extensive conservation of genomic imbalances in canine transmissible venereal tumors (CTVT) detected by microarray-based CGH analysis. Chromosome Res. 2009, 17: 927-934. 10.1007/s10577-009-9080-8.
113. McCallum H, Jones M, Hawkins C, Hamede R, Lachish S, Sinn DL, Beeton N, Lazenby B: Transmission dynamics of Tasmanian devil facial tumor disease may lead to disease-induced extinction. Ecology. 2009, 90: 3379-3392. 10.1890/08-1763.1.
114. Kreiss A, Tovar C, Obendorf DL, Dun K, Woods GM: A murine xenograft model for a transmissible cancer in Tasmanian devils. Vet Pathol. 2011, 48: 475-481. 10.1177/0300985810380398.
115. Copper HL, Mackay CM, Banfield WG: Chromosome studies of a contagious reticulum cell sarcoma of the Syrian hamster. J Natl Cancer Inst. 1964, 33: 691-706.
116. Banfield WG, Woke PA, Mackay CM, Cooper HL: Mosquito transmission of a reticulum cell sarcoma of hamsters. Science. 1965, 148: 1239-1240. 10.1126/science.148.3674.1239.
117. Gartner HV, Seidl C, Luckenbach C, Schumm G, Seifried E, Ritter H, Bultmann B: Genetic analysis of a sarcoma accidentally transplanted from a patient to a surgeon. N Engl J Med. 1996, 335: 1494-1496. 10.1056/NEJM199611143352004.
118. Rebbeck CA, Thomas R, Breen M, Leroi AM, Burt A: Origins and evolution of a transmissible cancer. Evolution. 2009, 63: 2340-2349. 10.1111/j.1558-5646.2009.00724.x.
119. Rebbeck CA, Leroi AM, Burt A: Mitochondrial capture by a transmissible cancer. Science. 2011, 331: 303-10.1126/science.1197696.
120. Villanueva T: Metabolism: the mitochondria that wag the dog. Nat Rev Cancer. 2011, 11: 155-10.1038/nrc3026.
121. Stettner N, Brenner O, Eilam R, Harmelin A: Pegylated liposomal doxorubicin as a chemotherapeutic agent for treatment of canine transmissible venereal tumor in murine models. J Vet Med Sci. 2005, 67: 1133-1139. 10.1292/jvms.67.1133.
122. Spees JL, Olson SD, Whitney MJ, Prockop DJ: Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA. 2006, 103: 1283-1288. 10.1073/pnas.0510511103.
123. Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A, Becker K, Yates JR, Felding-Habermann B: Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 2007, 67: 1472-1486. 10.1158/0008-5472.CAN-06-3137.
124. Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP: 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: 1271-1286. 10.4161/cc.10.8.15330.
125. Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP: Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010, 9: 3506-3514. 10.4161/cc.9.17.12731.