Advertisement

Tumor Biology

, Volume 37, Issue 7, pp 8503–8514 | Cite as

CAF cellular glycolysis: linking cancer cells with the microenvironment

  • Amrita Roy
  • Soumen Bera
Review

Abstract

Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.

Keywords

Tumour microenvironment Cancer associated fibroblast Metabolism Glycolysis 

Notes

Acknowledgments

This work has been supported by research grant from the Department of Science and Technology, Govt. of India (Ref. SB/YS/LS-248/2013) and Department of Biotechnology, Govt. of India (Ref. 6242-P5/RGCB/PMD/DBT/SMNB/2015) to SB.

Compliance with ethical standards

Conflict of interest

None.

References

  1. 1.
    Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.PubMedGoogle Scholar
  2. 2.
    Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumour stroma. Exp Cell Res. 2010;316:1324–31.PubMedGoogle Scholar
  3. 3.
    Fang H, Declerck YA. Targeting the tumour microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 2013;73:4965–77.PubMedGoogle Scholar
  4. 4.
    Li X, Ma Q, Xu Q, Duan W, Lei J, Wu E. Targeting the cancer-stroma interaction: a potential approach for pancreatic cancer treatment. Curr Pharm Des. 2012;18:2404–15.PubMedPubMedCentralGoogle Scholar
  5. 5.
    El-Nikhely N, Larzabal L, Seeger W, Calvo A, Savai R. Tumour-stromal interactions in lung cancer: novel candidate targets for therapeutic intervention. Expert Opin Investig Drugs. 2012;21:1107–22.PubMedGoogle Scholar
  6. 6.
    Tchou J, Conejo-Garcia J. Targeting the tumour stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm. Adv Pharmacol. 2012;65:45–61.PubMedGoogle Scholar
  7. 7.
    De Veirman K, Rao L, De Bruyne E, Menu E, Van Valckenborgh E, Van Riet I, et al. Cancer associated fibroblasts and tumour growth: focus on multiple myeloma. Cancers (Basel). 2014;6:1363–81.Google Scholar
  8. 8.
    Rasanen K, Vaheri A. Activation of fibroblasts in cancer stroma. Exp Cell Res. 2010;316:2713–22.PubMedGoogle Scholar
  9. 9.
    Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumour-promoting cell type. Cell Cycle. 2006;5:1597–601.PubMedGoogle Scholar
  10. 10.
    Witz IP. The tumour microenvironment: the making of a paradigm. Cancer Microenviron. 2009;2 Suppl 1:9–17.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Bhome R, Bullock MD, Al Saihati HA, Goh RW, Primrose JN, Sayan AE, et al. A top-down view of the tumour microenvironment: structure, cells and signaling. Front Cell Dev Biol. 2015;3:33.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Vannucci L. Stroma as an active player in the development of the tumour microenvironment. Cancer Microenviron. 2015;8(3):159–66.Google Scholar
  13. 13.
    Schafer M, Werner S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol. 2008;9:628–38.PubMedGoogle Scholar
  14. 14.
    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 tumour stroma. Cell Cycle. 2009;8:3984–4001.PubMedGoogle Scholar
  15. 15.
    Chiarugi P, Cirri P. Metabolic exchanges within tumour microenvironment. Cancer Lett. 2015. doi: 10.1016/j.canlet.2015.10.027
  16. 16.
    Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, et al. Glycolytic cancer associated fibroblasts promote breast cancer tumour growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling. Cell Cycle. 2010;9:2412–22.PubMedGoogle Scholar
  17. 17.
    Chiavarina B, Whitaker-Menezes D, Martinez-Outschoorn UE, Witkiewicz AK, Birbe R, Howell A, et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumour growth. Cancer Biol Ther. 2011;12:1101–13.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Pacini N, Borziani F. Cancer stem cell theory and the Warburg effect, two sides of the same coin? Int J Mol Sci. 2014;15:8893–930.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Sanita P, Capulli M, Teti A, Galatioto GP, Vicentini C, Chiarugi P, et al. Tumour-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC Cancer. 2014;14:154.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Gonzalez CD, Alvarez S, Ropolo A, Rosenzvit C, Bagnes MF, Vaccaro MI. Autophagy, Warburg, and Warburg reverse effects in human cancer. Biomed Res Int. 2014;2014:926729.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Suh DH, Kim HS, Kim B, Song YS. Metabolic orchestration between cancer cells and tumour microenvironment as a co-evolutionary source of chemoresistance in ovarian cancer: a therapeutic implication. Biochem Pharmacol. 2014;92:43–54.PubMedGoogle Scholar
  22. 22.
    Martinez-Outschoorn U, Sotgia F, Lisanti MP. Tumour microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Semin Oncol. 2014;41:195–216.PubMedGoogle Scholar
  23. 23.
    Bainbridge P. Wound healing and the role of fibroblasts. J Wound Care. 2013;22:407–8. 10–12.PubMedGoogle Scholar
  24. 24.
    Darby IA, Laverdet B, Bonte F, Desmouliere A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301–11.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283–9.PubMedGoogle Scholar
  26. 26.
    Trabold O, Wagner S, Wicke C, Scheuenstuhl H, Hussain MZ, Rosen N, et al. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 2003;11:504–9.PubMedGoogle Scholar
  27. 27.
    Wagner S, Hussain MZ, Hunt TK, Bacic B, Becker HD. Stimulation of fibroblast proliferation by lactate-mediated oxidants. Wound Repair Regen. 2004;12:368–73.PubMedGoogle Scholar
  28. 28.
    Anderson GR, Stoler DL, Scarcello LA. Normal fibroblasts responding to anoxia exhibit features of the malignant phenotype. J Biol Chem. 1989;264:14885–92.PubMedGoogle Scholar
  29. 29.
    Ao M, Franco OE, Park D, Raman D, Williams K, Hayward SW. Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res. 2007;67:4244–53.PubMedGoogle Scholar
  30. 30.
    Casey TM, Eneman J, Crocker A, White J, Tessitore J, Stanley M, et al. Cancer associated fibroblasts stimulated by transforming growth factor beta1 (TGF-beta 1) increase invasion rate of tumour cells: a population study. Breast Cancer Res Treat. 2008;110:39–49.PubMedGoogle Scholar
  31. 31.
    Rosenthal E, McCrory A, Talbert M, Young G, Murphy-Ullrich J, Gladson C. Elevated expression of TGF-beta1 in head and neck cancer-associated fibroblasts. Mol Carcinog. 2004;40:116–21.PubMedGoogle Scholar
  32. 32.
    Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, et al. Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell Rep. 2015;10:1335–48.PubMedGoogle Scholar
  33. 33.
    Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129–55.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Dvorak HF. Tumours: wounds that do not heal. Similarities between tumour stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.PubMedGoogle Scholar
  35. 35.
    Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res. 1999;250:273–83.PubMedGoogle Scholar
  36. 36.
    Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2010;43:146–55.PubMedGoogle Scholar
  37. 37.
    Yamaguchi H, Sakai R. Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers (Basel). 2015;7:2054–62.Google Scholar
  38. 38.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumour growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.PubMedGoogle Scholar
  39. 39.
    Hu M, Peluffo G, Chen H, Gelman R, Schnitt S, Polyak K. Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Natl Acad Sci U S A. 2009;106:3372–7.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Wen S, Niu Y, Yeh S, Chang C. BM-MSCs promote prostate cancer progression via the conversion of normal fibroblasts to cancer-associated fibroblasts. Int J Oncol. 2015;47:719–27.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol. 2014;16:889–901.PubMedGoogle Scholar
  42. 42.
    Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K, Hayakawa Y, Takahashi R, et al. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS One. 2013;8:e60914.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, et al. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2015;54:554–65.PubMedGoogle Scholar
  44. 44.
    Erez N, Glanz S, Raz Y, Avivi C, Barshack I. Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumours. Biochem Biophys Res Commun. 2013;437:397–402.PubMedGoogle Scholar
  45. 45.
    Lin ZY, Chuang WL. Hepatocellular carcinoma cells cause different responses in expressions of cancer-promoting genes in different cancer-associated fibroblasts. Kaohsiung J Med Sci. 2013;29:312–8.PubMedGoogle Scholar
  46. 46.
    Arshad A, Chung WY, Steward W, Metcalfe MS, Dennison AR. Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil. HPB (Oxford). 2013;15:428–32.Google Scholar
  47. 47.
    Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, et al. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch. 2010;77:97–105.PubMedGoogle Scholar
  48. 48.
    Lee KW, Yeo SY, Sung CO, Kim SH. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res. 2015;75:73–85.PubMedGoogle Scholar
  49. 49.
    Khan MA, Chen HC, Zhang D, Fu J. Twist: a molecular target in cancer therapeutics. Tumour Biol. 2013;34:2497–506.PubMedGoogle Scholar
  50. 50.
    Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME, et al. MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2012;2:1100–8.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Li P, Shan JX, Chen XH, Zhang D, Su LP, Huang XY, et al. Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumour microenvironment. Cell Res. 2015;25:588–603.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Zeng Z, Hu P, Tang X, Zhang H, Du Y, Wen S, et al. Dectection and analysis of miRNA expression in breast cancer-associated fibroblasts. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014;30:1071–5.PubMedGoogle Scholar
  53. 53.
    Sun P, Hu JW, Xiong WJ, Mi J. miR-186 regulates glycolysis through Glut1 during the formation of cancer-associated fibroblasts. Asian Pac J Cancer Prev. 2014;15:4245–50.PubMedGoogle Scholar
  54. 54.
    Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumour progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002–11.PubMedGoogle Scholar
  55. 55.
    Li H, Zhang J, Chen SW, Liu LL, Li L, Gao F, et al. Cancer-associated fibroblasts provide a suitable microenvironment for tumour development and progression in oral tongue squamous cancer. J Transl Med. 2015;13:198.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Bruzzese F, Hagglof C, Leone A, Sjoberg E, Roca MS, Kiflemariam S, et al. Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Res. 2014;74:3408–17.PubMedGoogle Scholar
  57. 57.
    Teichgraber V, Monasterio C, Chaitanya K, Boger R, Gordon K, Dieterle T, et al. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumour progression in vitro. Adv Med Sci. 2015;60:264–72.PubMedGoogle Scholar
  58. 58.
    Schwarz-Cruz YCA, Espinosa M, Maldonado V, Melendez-Zajgla J. Advances in the knowledge of breast cancer stem cells. A review. Histol Histopathol. 2015;0:11718.Google Scholar
  59. 59.
    Leon G, MacDonagh L, Finn SP, Cuffe S, Barr MP. Cancer stem cells in drug resistant lung cancer: targeting cell surface markers and signaling pathways. Pharmacol Ther. 2016;158:71–90.Google Scholar
  60. 60.
    Bertolini G, D’Amico L, Moro M, Landoni E, Perego P, Miceli R, et al. Microenvironment-modulated metastatic CD133+/CXCR4+/EpCAM- lung cancer-initiating cells sustain tumour dissemination and correlate with poor prognosis. Cancer Res. 2015;75:3636–49.PubMedGoogle Scholar
  61. 61.
    Peiris-Pages M, Sotgia F, Lisanti MP. Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine hedgehog-GLI signalling in breast cancer cells. Oncotarget. 2015;6:10728–45.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.PubMedGoogle Scholar
  63. 63.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.PubMedGoogle Scholar
  64. 64.
    Charafe-Jauffret E, Ginestier C, Birnbaum D. Breast cancer stem cells: tools and models to rely on. BMC Cancer. 2009;9:202.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Oliveira LR, Jeffrey SS, Ribeiro-Silva A. Stem cells in human breast cancer. Histol Histopathol. 2010;25:371–85.PubMedGoogle Scholar
  66. 66.
    Yoshida GJ, Saya H. Therapeutic strategies targeting cancer stem cells. Cancer Sci. 2016;107:5–11.PubMedGoogle Scholar
  67. 67.
    Jiang R, Niu X, Huang Y, Wang X. β-Catenin is important for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma. Acta Biochim Biophys Sin (Shanghai). 2016;48(3):229–37.Google Scholar
  68. 68.
    Jiang Z, Hao Y, Ding X, Zhang Z, Liu P, Wei X, et al. The effects and mechanisms of SLC34A2 on tumorigenicity in human non-small cell lung cancer stem cells. Tumour Biol. 2016. doi: 10.1007/s13277-016-4928-y
  69. 69.
    Inoue H, Takahashi H, Hashimura M, Eshima K, Akiya M, Matsumoto T, et al. Cooperation of Sox4 with beta-catenin/p300 complex in transcriptional regulation of the Slug gene during divergent sarcomatous differentiation in uterine carcinosarcoma. BMC Cancer. 2015;16:53.Google Scholar
  70. 70.
    Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.PubMedGoogle Scholar
  71. 71.
    Yang Z, Zhao T, Liu H, Zhang L. Ginsenoside Rh2 inhibits hepatocellular carcinoma through beta-catenin and autophagy. Sci Rep. 2016;6:19383.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Li M, Hale JS, Rich JN, Ransohoff RM, Lathia JD. Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair. Trends Neurosci. 2012;35:619–28.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Khorramdelazad H, Bagheri V, Hassanshahi G, Zeinali M, Vakilian A. New insights into the role of stromal cell-derived factor 1 (SDF-1/CXCL12) in the pathophysiology of multiple sclerosis. J Neuroimmunol. 2016;290:70–5.PubMedGoogle Scholar
  74. 74.
    Shan S, Lv Q, Zhao Y, Liu C, Sun Y, Xi K, et al. Wnt/beta-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells. Int J Clin Exp Pathol. 2015;8:12357–67.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.PubMedGoogle Scholar
  76. 76.
    Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM. The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med. 2003;167:1676–86.PubMedGoogle Scholar
  77. 77.
    Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res. 2013;3:46–57.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumour-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17:135–47.PubMedGoogle Scholar
  79. 79.
    Gorchs L, Hellevik T, Bruun JA, Camilio KA, Al-Saad S, Stuge TB, et al. Cancer-associated fibroblasts from lung tumours maintain their immunosuppressive abilities after high-dose irradiation. Front Oncol. 2015;5:87.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumour microenvironment and progression. Trends Immunol. 2010;31:220–7.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Liu FL, Mo EP, Yang L, Du J, Wang HS, Zhang H, et al. Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumour microenvironment. Oncotarget. 2016;7(4):4122–41.Google Scholar
  82. 82.
    Bagordakis E, Sawazaki-Calone I, Macedo CC, Carnielli CM, de Oliveira CE, Rodrigues PC, et al. Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures. Tumour Biol. 2016. doi: 10.1007/s13277-015-4629-y
  83. 83.
    Chen ZY, Wang PW, Shieh DB, Chiu KY, Liou YM. Involvement of gelsolin in TGF-beta 1 induced epithelial to mesenchymal transition in breast cancer cells. J Biomed Sci. 2015;22:90.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Kulbe H, Chakravarty P, Leinster DA, Charles KA, Kwong J, Thompson RG, et al. A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res. 2012;72:66–75.PubMedGoogle Scholar
  85. 85.
    Orr B, Grace OC, Brown P, Riddick AC, Stewart GD, Franco OE, et al. Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1. Dis Model Mech. 2013;6:530–6.PubMedGoogle Scholar
  86. 86.
    Hassona Y, Cirillo N, Heesom K, Parkinson EK, Prime SS. Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion. Br J Cancer. 2014;111:1230–7.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Yeung TL, Leung CS, Wong KK, Samimi G, Thompson MS, Liu J, et al. TGF-beta modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Res. 2013;73:5016–28.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Nagura M, Matsumura N, Baba T, Murakami R, Kharma B, Hamanishi J, et al. Invasion of uterine cervical squamous cell carcinoma cells is facilitated by locoregional interaction with cancer-associated fibroblasts via activating transforming growth factor-beta. Gynecol Oncol. 2015;136:104–11.PubMedGoogle Scholar
  89. 89.
    Maller O, DuFort CC, Weaver VM. YAP forces fibroblasts to feel the tension. Nat Cell Biol. 2013;15:570–2.PubMedGoogle Scholar
  90. 90.
    Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637–46.PubMedGoogle Scholar
  91. 91.
    Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, et al. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res. 2009;7:1438–45.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S, et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J. 2012;31:1985–98.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 2002;62:5881–7.PubMedGoogle Scholar
  94. 94.
    Bagui S, Ray M, Ray S. Glyceraldehyde-3-phosphate dehydrogenase from Ehrlich ascites carcinoma cells its possible role in the high glycolysis of malignant cells. Eur J Biochem. 1999;262:386–95.PubMedGoogle Scholar
  95. 95.
    Patra S, Ghosh S, Bera S, Roy A, Ray S, Ray M. Molecular characterization of tumor associated glyceraldehyde-3-phosphate dehydrogenase. Biochemistry (Mosc). 2009;74:717–27.Google Scholar
  96. 96.
    Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A. 1997;94:6658–63.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, et al. p53 regulates mitochondrial respiration. Science. 2006;312:1650–3.PubMedGoogle Scholar
  98. 98.
    Bonuccelli G, Avnet S, Grisendi G, Salerno M, Granchi D, Dominici M, et al. Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells. Oncotarget. 2014;5:7575–88.PubMedPubMedCentralGoogle Scholar
  99. 99.
    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.PubMedGoogle Scholar
  100. 100.
    Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res. 2015;34:111.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70:1469–80.PubMedGoogle Scholar
  102. 102.
    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.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Cotán D, Paz MV, Alcocer-Gómez E, Garrido-Maraver J, Oropesa-Ávila M, de la Mata M, et al. AMPK as a target in rare diseases. Curr Drug Targets. 2016. (in press)Google Scholar
  104. 104.
    Zadra G, Batista JL, Loda M. Dissecting the dual role of AMPK in cancer: from experimental to human studies. Mol Cancer Res. 2015;13:1059–72.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Scaglia N, Tyekucheva S, Zadra G, Photopoulos C, Loda M. De novo fatty acid synthesis at the mitotic exit is required to complete cellular division. Cell Cycle. 2014;13:859–68.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17:113–24.PubMedGoogle Scholar
  107. 107.
    Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, et al. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell. 2013;52:161–72.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014;74:4783–95.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485:661–5.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Zhong D, Liu X, Khuri FR, Sun SY, Vertino PM, Zhou W. LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins. Cancer Res. 2008;68:7270–7.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Lang F, Foller M. Regulation of ion channels and transporters by AMP-activated kinase (AMPK). Channels (Austin). 2014;8:20–8.Google Scholar
  112. 112.
    Fraser SA, Davies M, Katerelos M, Gleich K, Choy SW, Steel R, et al. Activation of AMPK reduces the co-transporter activity of NKCC1. Mol Membr Biol. 2014;31:95–102.PubMedGoogle Scholar
  113. 113.
    Yoshida GJ, Saya H. EpCAM expression in the prostate cancer makes the difference in the response to growth factors. Biochem Biophys Res Commun. 2014;443:239–45.PubMedGoogle Scholar
  114. 114.
    Laderoute KR, Calaoagan JM, Chao WR, Dinh D, Denko N, Duellman S, et al. 52032-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors. J Biol Chem. 2014;289:22850–64.PubMedPubMedCentralGoogle Scholar
  115. 115.
    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.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Shi H, Jiang H, Wang L, Cao Y, Liu P, Xu X, et al. Overexpression of monocarboxylate anion transporter 1 and 4 in T24-induced cancer-associated fibroblasts regulates the progression of bladder cancer cells in a 3D microfluidic device. Cell Cycle. 2015;14:3058–65.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12:152.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Ros S, Schulze A. Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 2013;1:8.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hu JW, Sun P, Zhang DX, Xiong WJ, Mi J. Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts. Cell Signal. 2014;26:2210–6.PubMedGoogle Scholar
  120. 120.
    Courteau L, Crasto J, Hassanzadeh G, Baird SD, Hodgins J, Liwak-Muir U, et al. Hexokinase 2 controls cellular stress response through localization of an RNA-binding protein. Cell Death Dis. 2015;6:e1837.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Zhou Y, Lu N, Qiao C, Ni T, Li Z, Yu B, et al. FV-429 induces apoptosis and inhibits glycolysis by inhibiting Akt-mediated phosphorylation of hexokinase II in MDA-MB-231 cells. Mol Carcinog. 2015. doi: 10.1002/mc.22374
  122. 122.
    Henry E, Fung N, Liu J, Drakakaki G, Coaker G. Beyond glycolysis: GAPDHs are multi-functional enzymes involved in regulation of ROS, autophagy, and plant immune responses. PLoS Genet. 2015;11:e1005199.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Suarez S, McCollum GW, Jayagopal A, Penn JS. High glucose-induced retinal pericyte apoptosis depends on association of GAPDH and Siah1. J Biol Chem. 2015;290:28311–20.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Donnelly RP, Finlay DK. Glucose, glycolysis and lymphocyte responses. Mol Immunol. 2015;68:513–9.PubMedGoogle Scholar
  125. 125.
    Volkenhoff A, Weiler A, Letzel M, Stehling M, Klambt C, Schirmeier S. Glial glycolysis is essential for neuronal survival in Drosophila. Cell Metab. 2015;22:437–47.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.School of Life SciencesB. S. Abdur Rahman UniversityChennaiIndia

Personalised recommendations