Abstract
The canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas. Wnt-induced epidermal growth factor receptor/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, Wnt-induced signal transducers and activators of transcription 3 (STAT3) signaling, and Wnt/β-catenin target gene transduction (c-Myc) can activate HIF-1α in a hypoxia-independent manner. The PI3K/Akt/mammalian target of rapamycin pathway activates HIF-1α through eukaryotic translation initiation factor 4E-binding protein 1 and STAT3. The β-catenin/T-cell factor 4 complex directly binds to STAT3 and activates HIF-1α, which up-regulates the Wnt/β-catenin target genes cyclin D1 and c-Myc in a positive feedback loop. Phosphorylated STAT3 by interleukin-6 or leukemia inhibitory factor activates HIF-1α even under normoxic conditions. The activation of the Wnt/β-catenin pathway induces, via the Wnt target genes c-Myc and cyclin D1 or via HIF-1α, gene transactivation encoding aerobic glycolysis enzymes, such as glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production, as the primary alternative of ATP, at all oxygen levels, even in normoxic conditions. Lactate released by glioma cells via the monocarboxylate lactate transporter-1 up-regulated by HIF-1α and lactate anion activates HIF-1α in normoxic endothelial cells by inhibiting HIF-1α prolyl hydroxylation and preventing HIF labeling by the von Hippel-Lindau protein. Increased lactate with acid environment and HIF-1α overexpression induce the vascular endothelial growth factor (VEGF) pathway of vasculogenesis and angiogenesis under normoxic conditions. Hypoxia and acidic pH have no synergistic effect on VEGF transcription.
Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.
References
Aberle, H., Bauer, A., Stappert, J., Kispert, A., and Kemler, R. (1997). β-Catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16, 3797–3804.10.1093/emboj/16.13.3797Search in Google Scholar PubMed
Al-Harthi, L. (2012). Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. J. Neuroimmune Pharmacol. 7, 725–730.10.1007/s11481-012-9412-xSearch in Google Scholar PubMed
Ambacher, K.K., Pitzul, K.B., Karajgikar, M., Hamilton, A., Ferguson, S.S., and Cregan, S.P. (2012). The JNK- and AKT/GSK3β-signaling pathways converge to regulate Puma induction and neuronal apoptosis induced by trophic factor deprivation. PLoS One 7, e46885.10.1371/journal.pone.0046885Search in Google Scholar PubMed
Anastasiou, D., Yu, Y., Israelsen, W.J., Jiang, J.-K., Boxer, M.B., Hong, B.S., Tempel, W., Dimov, S., Shen, M., Jha, A., et al. (2012). Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat. Chem. Biol. 8, 839–847.10.1038/nchembio.1060Search in Google Scholar PubMed
Angers, S. and Moon, R.T. (2009). Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10, 468–477.10.1038/nrm2717Search in Google Scholar PubMed
Arbab, A.S. (2012). Activation of alternative pathways of angiogenesis and involvement of stem cells following anti-angiogenesis treatment in glioma. Histol. Histopathol. 27, 549–557.Search in Google Scholar PubMed
Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., and Isner, J.M. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967.10.1126/science.275.5302.964Search in Google Scholar PubMed
Ashizawa, K., McPhie, P., Lin, K.H., and Cheng, S.Y. (1991). An in vitro novel mechanism of regulating the activity of pyruvate kinase M2 by thyroid hormone and fructose 1,6-bisphosphate. Biochemistry (Mosc.) 30, 7105–7111.10.1021/bi00243a010Search in Google Scholar
Bao, L., Kimzey, A., Sauter, G., Sowadski, J.M., Lu, K.P., and Wang, D.-G. (2004). Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am. J. Pathol. 164, 1727–1737.10.1016/S0002-9440(10)63731-5Search in Google Scholar PubMed
Bar, E.E., Lin, A., Mahairaki, V., Matsui, W., and Eberhart, C.G. (2010). Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am. J. Pathol. 177, 1491–1502.10.2353/ajpath.2010.091021Search in Google Scholar PubMed PubMed Central
Baumann, F., Leukel, P., Doerfelt, A., Beier, C.P., Dettmer, K., Oefner, P.J., Kastenberger, M., Kreutz, M., Nickl-Jockschat, T., Bogdahn, U., et al. (2009). Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2. Neuro-Oncology 11, 368–380.10.1215/15228517-2008-106Search in Google Scholar PubMed PubMed Central
Beckert, S., Farrahi, F., Aslam, R.S., Scheuenstuhl, H., Königsrainer, A., Hussain, M.Z., and Hunt, T.K. (2006). Lactate stimulates endothelial cell migration. Wound Repair Regen. Off. Publ. Wound Heal. Soc. Eur. Tissue Repair Soc. 14, 321–324.10.1111/j.1743-6109.2006.00127.xSearch in Google Scholar PubMed
Bensinger, S.J. and Christofk, H.R. (2012). New aspects of the Warburg effect in cancer cell biology. Semin. Cell Dev. Biol. 23, 352–361.10.1016/j.semcdb.2012.02.003Search in Google Scholar PubMed
Bergers, G. and Song, S. (2005). The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology 7, 452–464.10.1215/S1152851705000232Search in Google Scholar PubMed PubMed Central
Berra, E., Ginouvès, A., and Pouysségur, J. (2006). The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. 7, 41–45.10.1038/sj.embor.7400598Search in Google Scholar PubMed PubMed Central
Bonnet, S., Archer, S.L., Allalunis-Turner, J., Haromy, A., Beaulieu, C., Thompson, R., Lee, C.T., Lopaschuk, G.D., Puttagunta, L., Bonnet, S., et al. (2007). A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51.10.1016/j.ccr.2006.10.020Search in Google Scholar PubMed
Bos, R., van Der Hoeven, J.J.M., van Der Wall, E., van Der Groep, P., van Diest, P.J., Comans, E.F.I., Joshi, U., Semenza, G.L., Hoekstra, O.S., Lammertsma, A.A., et al. (2002). Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J. Clin. Oncol. 20, 379–387.10.1200/JCO.2002.20.2.379Search in Google Scholar PubMed
Bouzier-Sore, A.K., Canioni, P., and Merle, M. (2001). Effect of exogenous lactate on rat glioma metabolism. J. Neurosci. Res. 65, 543–548.10.1002/jnr.1184Search in Google Scholar PubMed
Bowman, T., Garcia, R., Turkson, J., and Jove, R. (2000). STATs in oncogenesis. Oncogene 19, 2474–2488.10.1038/sj.onc.1203527Search in Google Scholar PubMed
Brabletz, T., Hlubek, F., Spaderna, S., Schmalhofer, O., Hiendlmeyer, E., Jung, A., and Kirchner, T. (2005). Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and β-catenin. Cells Tissues Organs 179, 56–65.10.1159/000084509Search in Google Scholar PubMed
Brahimi-Horn, M.C., Chiche, J., and Pouysségur, J. (2007). Hypoxia and cancer. J. Mol. Med. Berl. Ger. 85, 1301–1307.10.1007/s00109-007-0281-3Search in Google Scholar PubMed
Brooks, G.A. (2002). Lactate shuttles in nature. Biochem. Soc. Trans. 30, 258–264.10.1042/bst0300258Search in Google Scholar PubMed
Brooks, P.C., Clark, R.A., and Cheresh, D.A. (1994). Requirement of vascular integrin αvβ3 for angiogenesis. Science 264, 569–571.10.1126/science.7512751Search in Google Scholar
Brugarolas, J.B., Vazquez, F., Reddy, A., Sellers, W.R., and Kaelin, W.G. (2003). TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158.10.1016/S1535-6108(03)00187-9Search in Google Scholar PubMed
Burgner, J.W. and Ray, W.J. (1984). On the origin of the lactate dehydrogenase induced rate effect. Biochemistry (Mosc.) 23, 3636–3648.10.1021/bi00311a010Search in Google Scholar PubMed
Burke, J.E. and Williams, R.L. (2015). Synergy in activating class I PI3Ks. Trends Biochem. Sci. 40, 88–100.10.1016/j.tibs.2014.12.003Search in Google Scholar PubMed
Carmeliet, P. (2000). Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 6, 389–395.10.1038/74651Search in Google Scholar PubMed
Carro, M.S., Lim, W.K., Alvarez, M.J., Bollo, R.J., Zhao, X., Snyder, E.Y., Sulman, E.P., Anne, S.L., Doetsch, F., Colman, H., et al. (2010). The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318–325.10.1038/nature08712Search in Google Scholar PubMed PubMed Central
Catlett-Falcone, R., Dalton, W.S., and Jove, R. (1999). STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. Curr. Opin. Oncol. 11, 490–496.10.1097/00001622-199911000-00010Search in Google Scholar PubMed
Cetin, B., Afsar, B., Deger, S.M., Gonul, I.I., Gumusay, O., Ozet, A., Benekli, M., Coskun, U., and Buyukberber, S. (2014). Association between hemoglobin, calcium, and lactate dehydrogenase variability and mortality among metastatic renal cell carcinoma. Int. Urol. Nephrol. 46, 1081–1087.10.1007/s11255-013-0613-xSearch in Google Scholar PubMed
Chakravarti, A., Dicker, A., and Mehta, M. (2004). The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. Int. J. Radiat. Oncol. 58, 927–931.10.1016/j.ijrobp.2003.09.092Search in Google Scholar PubMed
Chang, L.K., Garcia-Cardena, G., Farnebo, F., Fannon, M., Chen, E.J., Butterfield, C., Moses, M.A., Mulligan, R.C., Folkman, J., and Kaipainen, A. (2004). Dose-dependent response of FGF-2 for lymphangiogenesis. Proc. Natl. Acad. Sci. USA 101, 11658–11663.10.1073/pnas.0404272101Search in Google Scholar PubMed PubMed Central
Chen, Z., Lu, W., Garcia-Prieto, C., and Huang, P. (2007). The Warburg effect and its cancer therapeutic implications. J. Bioenerg. Biomembr. 39, 267–274.10.1007/s10863-007-9086-xSearch in Google Scholar PubMed
Chi, J.-T., Wang, Z., Nuyten, D.S.A., Rodriguez, E.H., Schaner, M.E., Salim, A., Wang, Y., Kristensen, G.B., Helland, A., Børresen-Dale, A.L., et al. (2006). Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 3, e47.10.1371/journal.pmed.0030047Search in Google Scholar PubMed PubMed Central
Chung, A.S., Lee, J., and Ferrara, N. (2010). Targeting the tumour vasculature: insights from physiological angiogenesis. Nat. Rev. Cancer 10, 505–514.10.1038/nrc2868Search in Google Scholar PubMed
Clara, C.A., Marie, S.K.N., de Almeida, J.R.W., Wakamatsu, A., Oba-Shinjo, S.M., Uno, M., Neville, M., and Rosemberg, S. (2014). Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma: angiogenesis and glioblastoma. Neuropathology 34, 343–352.10.1111/neup.12111Search in Google Scholar PubMed
Clevers, H. (2006). Wnt/β-catenin signaling in development and disease. Cell 127, 469–480.10.1016/j.cell.2006.10.018Search in Google Scholar PubMed
Coffer, P.J., Koenderman, L., and de Groot, R.P. (2000). The role of STATs in myeloid differentiation and leukemia. Oncogene 19, 2511–2522.10.1038/sj.onc.1203479Search in Google Scholar PubMed
Constant, J.S., Feng, J.J., Zabel, D.D., Yuan, H., Suh, D.Y., Scheuenstuhl, H., Hunt, T.K., and Hussain, M.Z. (2000). Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen. 8, 353–360.10.1111/j.1524-475X.2000.00353.xSearch in Google Scholar PubMed
Corada, M., Nyqvist, D., Orsenigo, F., Caprini, A., Giampietro, C., Taketo, M.M., Iruela-Arispe, M.L., Adams, R.H., and Dejana, E. (2010). The Wnt/β-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev. Cell 18, 938–949.10.1016/j.devcel.2010.05.006Search in Google Scholar PubMed PubMed Central
D’Arcangelo, D., Facchiano, F., Barlucchi, L.M., Melillo, G., Illi, B., Testolin, L., Gaetano, C., and Capogrossi, M.C. (2000). Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. Circ. Res. 86, 312–318.10.1161/01.RES.86.3.312Search in Google Scholar PubMed
Dan, H.C., Antonia, R.J., and Baldwin, A.S. (2016). PI3K/Akt promotes feedforward mTORC2 activation through IKKα. Oncotarget 7, 21064–21075.10.18632/oncotarget.8383Search in Google Scholar PubMed PubMed Central
Darnell, J.E. (1997). STATs and gene regulation. Science 277, 1630–1635.10.1126/science.277.5332.1630Search in Google Scholar PubMed
De Saedeleer, C.J., Copetti, T., Porporato, P.E., Verrax, J., Feron, O., and Sonveaux, P. (2012). Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One 7, e46571.10.1371/journal.pone.0046571Search in Google Scholar PubMed PubMed Central
Dekanty, A. (2005). The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-/Sima. J. Cell Sci. 118, 5431–5441.10.1242/jcs.02648Search in Google Scholar PubMed
Denysenko, T., Annovazzi, L., Cassoni, P., Melcarne, A., Mellai, M., and Schiffer, D. (2016). Wnt/β-catenin signaling pathway and downstream modulators in low- and high-grade glioma. Cancer Genom. Proteom. 13, 31–45.Search in Google Scholar
Dhup, S., Dadhich, R.K., Porporato, P.E., and Sonveaux, P. (2012). Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr. Pharm. Des. 18, 1319–1330.10.2174/138161212799504902Search in Google Scholar PubMed
Dibble, C.C. and Cantley, L.C. (2015). Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 25, 545–555.10.1016/j.tcb.2015.06.002Search in Google Scholar PubMed PubMed Central
Duan, Y., Zhao, X., Ren, W., Wang, X., Yu, K.-F., Li, D., Zhang, X., and Zhang, Q. (2013). Antitumor activity of dichloroacetate on C6 glioma cell: in vitro and in vivo evaluation. Oncotargets Ther. 6, 189–198.10.2147/OTT.S40992Search in Google Scholar PubMed PubMed Central
Dumont, D.J., Gradwohl, G., Fong, G.H., Puri, M.C., Gertsenstein, M., Auerbach, A., and Breitman, M.L. (1994). Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909.10.1101/gad.8.16.1897Search in Google Scholar PubMed
Dunlop, E.A., Dodd, K.M., Seymour, L.A., and Tee, A.R. (2009). Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cell. Signal. 21, 1073–1084.10.1016/j.cellsig.2009.02.024Search in Google Scholar PubMed
Düvel, K., Yecies, J.L., Menon, S., Raman, P., Lipovsky, A.I., Souza, A.L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183.10.1016/j.molcel.2010.06.022Search in Google Scholar PubMed PubMed Central
Efeyan, A. and Sabatini, D.M. (2013). Nutrients and growth factors in mTORC1 activation. Biochem. Soc. Trans. 41, 902–905.10.1042/BST20130063Search in Google Scholar PubMed
Eichten, A., Hyun, W.C., and Coussens, L.M. (2007). Distinctive features of angiogenesis and lymphangiogenesis determine their functionality during de novo tumor development. Cancer Res. 67, 5211–5220.10.1158/0008-5472.CAN-06-4676Search in Google Scholar PubMed
El Hallani, S., Boisselier, B., Peglion, F., Rousseau, A., Colin, C., Idbaih, A., Marie, Y., Mokhtari, K., Thomas, J.L., Eichmann, A., et al. (2010). A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain J. Neurol. 133, 973–982.10.1093/brain/awq044Search in Google Scholar
Fajas, L., Auboeuf, D., Raspé, E., Schoonjans, K., Lefebvre, A.M., Saladin, R., Najib, J., Laville, M., Fruchart, J.C., Deeb, S., et al. (1997). The organization, promoter analysis, and expression of the human PPARγ gene. J. Biol. Chem. 272, 18779–18789.10.1074/jbc.272.30.18779Search in Google Scholar PubMed
Fantin, V.R., St-Pierre, J., and Leder, P. (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434.10.1016/j.ccr.2006.04.023Search in Google Scholar PubMed
Faure Vigny, H., Heddi, A., Giraud, S., Chautard, D., and Stepien, G. (1996). Expression of oxidative phosphorylation genes in renal tumors and tumoral cell lines. Mol. Carcinog. 16, 165–172.10.1002/(SICI)1098-2744(199607)16:3<165::AID-MC7>3.0.CO;2-GSearch in Google Scholar PubMed
Feng, Z., Zhang, H., Levine, A.J., and Jin, S. (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA 102, 8204–8209.10.1073/pnas.0502857102Search in Google Scholar
Ferrara, N. and Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967–974.10.1038/nature04483Search in Google Scholar PubMed
Firth, J.D., Ebert, B.L., and Ratcliffe, P.J. (1995). Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J. Biol. Chem. 270, 21021–21027.10.1074/jbc.270.36.21021Search in Google Scholar PubMed
Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819.10.1182/blood-2006-07-035972Search in Google Scholar
Folkins, C., Shaked, Y., Man, S., Tang, T., Lee, C.R., Zhu, Z., Hoffman, R.M., and Kerbel, R.S. (2009). Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res. 69, 7243–7251.10.1158/0008-5472.CAN-09-0167Search in Google Scholar PubMed
Folkman, J. and Shing, Y. (1992). Angiogenesis. J. Biol. Chem. 267, 10931–10934.10.1016/S0021-9258(19)49853-0Search in Google Scholar PubMed
Formby, B. and Stern, R. (2003). Lactate-sensitive response elements in genes involved in hyaluronan catabolism. Biochem. Biophys. Res. Commun. 305, 203–208.10.1016/S0006-291X(03)00723-XSearch in Google Scholar PubMed
Francescone, R., Scully, S., Bentley, B., Yan, W., Taylor, S.L., Oh, D., Moral, L., and Shao, R. (2012). Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation. J. Biol. Chem. 287, 24821–24831.10.1074/jbc.M111.334540Search in Google Scholar PubMed PubMed Central
Fuhler, G.M., Tyl, M.R., Olthof, S.G.M., Lyndsay Drayer, A., Blom, N., and Vellenga, E. (2009). Distinct roles of the mTOR components Rictor and Raptor in MO7e megakaryocytic cells. Eur. J. Haematol. 83, 235–245.10.1111/j.1600-0609.2009.01263.xSearch in Google Scholar PubMed
Fukumura, D., Xu, L., Chen, Y., Gohongi, T., Seed, B., and Jain, R.K. (2001). Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 61, 6020–6024.Search in Google Scholar PubMed
Gan, X., Wang, J., Su, B., and Wu, D. (2011). Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 286, 10998–11002.10.1074/jbc.M110.195016Search in Google Scholar PubMed PubMed Central
Gao, F., Yang, C.X., Mo, W., Liu, Y.W., and He, Y.Q. (2008). Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clin. Investig. Med. Med. Clin. Exp. 31, E106–E116.10.25011/cim.v31i3.3467Search in Google Scholar PubMed
Gatenby, R.A., Gawlinski, E.T., Gmitro, A.F., Kaylor, B., and Gillies, R.J. (2006). Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223.10.1158/0008-5472.CAN-05-4193Search in Google Scholar PubMed
Genasetti, A., Vigetti, D., Viola, M., Karousou, E., Moretto, P., Rizzi, M., Bartolini, B., Clerici, M., Pallotti, F., De Luca, G., et al. (2008). Hyaluronan and human endothelial cell behavior. Connect. Tissue Res. 49, 120–123.10.1080/03008200802148462Search in Google Scholar PubMed
Gershon, T.R., Crowther, A.J., Tikunov, A., Garcia, I., Annis, R., Yuan, H., Miller, C.R., Macdonald, J., Olson, J., and Deshmukh, M. (2013). Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab. 1, 2.10.1186/2049-3002-1-2Search in Google Scholar PubMed PubMed Central
Giatromanolaki, A., Sivridis, E., Gatter, K.C., Turley, H., Harris, A.L., Koukourakis, M.I., and Tumour and Angiogenesis Research Group. (2006). Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis. Gynecol. Oncol. 103, 912–918.10.1016/j.ygyno.2006.05.043Search in Google Scholar PubMed
Goerges, A.L. and Nugent, M.A. (2004). pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release. J. Biol. Chem. 279, 2307–2315.10.1074/jbc.M308482200Search in Google Scholar PubMed
Gohil, K. and Brooks, G.A. (2012). Exercise tames the wild side of the Myc network: a hypothesis. Am. J. Physiol. Endocrinol. Metab. 303, E18–E30.10.1152/ajpendo.00027.2012Search in Google Scholar PubMed
Gottfried, E., Kunz-Schughart, L.A., Ebner, S., Mueller-Klieser, W., Hoves, S., Andreesen, R., Mackensen, A., and Kreutz, M. (2006). Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021.10.1182/blood-2005-05-1795Search in Google Scholar PubMed
Green, H. and Goldberg, B. (1964). Collagen and cell protein synthesis by an established mammalian fibroblast line. Nature 204, 347–349.10.1038/204347a0Search in Google Scholar PubMed
Greijer, A.E., van der Groep, P., Kemming, D., Shvarts, A., Semenza, G.L., Meijer, G.A., Mackensen, A., and Kreutz, M. (2005). Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J. Pathol. 206, 291–304.10.1002/path.1778Search in Google Scholar PubMed
Griffiths, J.R. (1991). Are cancer cells acidic? Br. J. Cancer 64, 425–427.10.1038/bjc.1991.326Search in Google Scholar PubMed PubMed Central
Gruetter, R. (2003). Glycogen: the forgotten cerebral energy store. J. Neurosci. Res. 74, 179–183.10.1002/jnr.10785Search in Google Scholar PubMed
Haaga, J.R. and Haaga, R. (2013). Acidic lactate sequentially induced lymphogenesis, phlebogenesis, and arteriogenesis (A) hypothesis: lactate-triggered glycolytic vasculogenesis that occurs in normoxia or hypoxia and complements the traditional concept of hypoxia-based vasculogenesis. Surgery 154, 632–637.10.1016/j.surg.2013.03.007Search in Google Scholar PubMed
Haddad, N.M.N., Cavallerano, J.D., and Silva, P.S. (2013). von Hippel-Lindau disease: a genetic and clinical review. Semin. Ophthalmol. 28, 377–386.10.3109/08820538.2013.825281Search in Google Scholar PubMed
Han, L., Yang, Y., Yue, X., Huang, K., Liu, X., Pu, P., Jiang, H., Yan, W., Jiang, T., and Kang, C. (2010). Inactivation of PI3K/AKT signaling inhibits glioma cell growth through modulation of β-catenin-mediated transcription. Brain Res. 1366, 9–17.10.1016/j.brainres.2010.09.097Search in Google Scholar PubMed
Hardee, M.E. and Zagzag, D. (2012). Mechanisms of glioma-associated neovascularization. Am. J. Pathol. 181, 1126–1141.10.1016/j.ajpath.2012.06.030Search in Google Scholar PubMed
Harris, R.A., Tindale, L., and Cumming, R.C. (2014). Age-dependent metabolic dysregulation in cancer and Alzheimer’s disease. Biogerontology 15, 559–577.10.1007/s10522-014-9534-zSearch in Google Scholar PubMed
Harrison-Uy, S.J. and Pleasure, S.J. (2012). Wnt signaling and forebrain development. Cold Spring Harb. Perspect. Biol. 4, a008094.10.1101/cshperspect.a008094Search in Google Scholar PubMed
Hashimoto, T., Hussien, R., Oommen, S., Gohil, K., and Brooks, G.A. (2007). Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J. 21, 2602–2612.10.1096/fj.07-8174comSearch in Google Scholar PubMed
Hirschhaeuser, F., Sattler, U.G.A., and Mueller-Klieser, W. (2011). Lactate: a metabolic key player in cancer. Cancer Res. 71, 6921–6925.10.1158/0008-5472.CAN-11-1457Search in Google Scholar PubMed
Hitosugi, T., Kang, S., Vander Heiden, M.G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G.Z., et al. (2009). Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73.10.1126/scisignal.2000431Search in Google Scholar PubMed
Holash, J., Maisonpierre, P.C., Compton, D., Boland, P., Alexander, C.R., Zagzag, D., Yancopoulos, G.D., and Wiegand, S.J. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998.10.1126/science.284.5422.1994Search in Google Scholar PubMed
Horvath, C.M. (2000). STAT proteins and transcriptional responses to extracellular signals. Trends Biochem. Sci. 25, 496–502.10.1016/S0968-0004(00)01624-8Search in Google Scholar PubMed
Howell, J.J., Ricoult, S.J.H., Ben-Sahra, I., and Manning, B.D. (2013). A growing role for mTOR in promoting anabolic metabolism. Biochem. Soc. Trans. 41, 906–912.10.1042/BST20130041Search in Google Scholar PubMed
Hresko, R.C. and Mueckler, M. (2005). mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J. Biol. Chem. 280, 40406–40416.10.1074/jbc.M508361200Search in Google Scholar PubMed
Huang, L.E., Arany, Z., Livingston, D.M., and Bunn, H.F. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. J. Biol. Chem. 271, 32253–32259.10.1074/jbc.271.50.32253Search in Google Scholar PubMed
Huang, M., Page, C., Reynolds, R.K., and Lin, J. (2000). Constitutive activation of Stat 3 oncogene product in human ovarian carcinoma cells. Gynecol. Oncol. 79, 67–73.10.1006/gyno.2000.5931Search in Google Scholar PubMed
Huang, J., Dibble, C.C., Matsuzaki, M., and Manning, B.D. (2008). The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol. 28, 4104–4115.10.1128/MCB.00289-08Search in Google Scholar PubMed PubMed Central
Hunt, T.K., Aslam, R.S., Beckert, S., Wagner, S., Ghani, Q.P., Hussain, M.Z., Roy, S., and Sen, C.K. (2007). Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid. Redox Signal. 9, 1115–1124.10.1089/ars.2007.1674Search in Google Scholar PubMed PubMed Central
Hunt, T.K., Aslam, R., Hussain, Z., and Beckert, S. (2008). Lactate, with oxygen, incites angiogenesis. Adv. Exp. Med. Biol. 614, 73–80.10.1007/978-0-387-74911-2_9Search in Google Scholar PubMed
Hur, E.-M. and Zhou, F.-Q. (2010). GSK3 signalling in neural development. Nat. Rev. Neurosci. 11, 539–551.10.1038/nrn2870Search in Google Scholar PubMed PubMed Central
Ille, F. and Sommer, L. (2005). Wnt signaling: multiple functions in neural development. Cell. Mol. Life Sci. 62, 1100–1108.10.1007/s00018-005-4552-2Search in Google Scholar PubMed
Imamura, K. and Tanaka, T. (1972). Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies. J. Biochem. (Tokyo) 71, 1043–1051.10.1093/oxfordjournals.jbchem.a129852Search in Google Scholar PubMed
Israelsen, W.J., Dayton, T.L., Davidson, S.M., Fiske, B.P., Hosios, A.M., Bellinger, G., Li, J., Yu, Y., Sasaki, M., Horner, J.W., et al. (2013). PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397–409.10.1016/j.cell.2013.09.025Search in Google Scholar PubMed PubMed Central
Iyer, N.V., Kotch, L.E., Agani, F., Leung, S.W., Laughner, E., Wenger, R.H., Gassmann, M., Gearhart, J.D., Lawler, A.M., Yu, A.Y., et al. (1998). Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162.10.1101/gad.12.2.149Search in Google Scholar PubMed PubMed Central
Jensen, J.A., Hunt, T.K., Scheuenstuhl, H., and Banda, M.J. (1986). Effect of lactate, pyruvate, and pH on secretion of angiogenesis and mitogenesis factors by macrophages. Lab. Invest. J. Tech. Methods Pathol. 54, 574–578.Search in Google Scholar
Jha, M.K. and Suk, K. (2013). Pyruvate dehydrogenase kinase as a potential therapeutic target for malignant gliomas. Brain Tumor Res. Treat. 1, 57–63.10.14791/btrt.2013.1.2.57Search in Google Scholar PubMed PubMed Central
Jiang, Y., Li, X., Yang, W., Hawke, D.H., Zheng, Y., Xia, Y., Aldape, K., Wei, C., Guo, F., Chen, Y., et al. (2014). PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol. Cell 53, 75–87.10.1016/j.molcel.2013.11.001Search in Google Scholar PubMed PubMed Central
Jones, N., Iljin, K., Dumont, D.J., and Alitalo, K. (2001). Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat. Rev. Mol. Cell Biol. 2, 257–267.10.1038/35067005Search in Google Scholar PubMed
Jung, J.E., Lee, H.G., Cho, I.H., Chung, D.H., Yoon, S.-H., Yang, Y.M., Lee, J.W., Choi, S., Park, J.W., Ye, S.K., et al. (2005). STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J. 19, 1296–1298.10.1096/fj.04-3099fjeSearch in Google Scholar PubMed
Kaelin, W.G. (2005). The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb. Symp. Quant. Biol. 70, 159–166.10.1101/sqb.2005.70.001Search in Google Scholar PubMed
Kallio, P.J., Pongratz, I., Gradin, K., McGuire, J., and Poellinger, L. (1997). Activation of hypoxia-inducible factor 1α: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc. Natl. Acad. Sci. USA 94, 5667–5672.10.1073/pnas.94.11.5667Search in Google Scholar PubMed PubMed Central
Kang, S.-H., Yu, M.O., Park, K.-J., Chi, S.-G., Park, D.-H., and Chung, Y.-G. (2010). Activated STAT3 regulates hypoxia-induced angiogenesis and cell migration in human glioblastoma. Neurosurgery 67, 1386–1395; discussion 1395.10.1227/NEU.0b013e3181f1c0cdSearch in Google Scholar PubMed
Karsy, M., Guan, J., Jensen, R., Huang, L.E., and Colman, H. (2016). The impact of hypoxia and mesenchymal transition on glioblastoma pathogenesis and cancer stem cells regulation. World Neurosurg. 88, 222–236.10.1016/j.wneu.2015.12.032Search in Google Scholar PubMed
Kaur, B., Tan, C., Brat, D.J., Post, D.E., and Van Meir, E.G. (2004). Genetic and hypoxic regulation of angiogenesis in gliomas. J. Neurooncol. 70, 229–243.10.1007/s11060-004-2752-5Search in Google Scholar PubMed
Kaur, N., Chettiar, S., Rathod, S., Rath, P., Muzumdar, D., Shaikh, M.L., and Shiras, A. (2013). Wnt3a mediated activation of Wnt/β-catenin signaling promotes tumor progression in glioblastoma. Mol. Cell. Neurosci. 54, 44–57.10.1016/j.mcn.2013.01.001Search in Google Scholar PubMed
Ke, Q. and Costa, M. (2006). Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol. 70, 1469–1480.10.1124/mol.106.027029Search in Google Scholar PubMed
Keenan, M.M. and Chi, J.-T. (2015). Alternative fuels for cancer cells. Cancer J. Sudbury Mass 21, 49–55.10.1097/PPO.0000000000000104Search in Google Scholar
Kerbel, R.S. (2008). Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049.10.1056/NEJMra0706596Search in Google Scholar PubMed
Kim, J. and Dang, C.V. (2006). Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930.10.1158/0008-5472.CAN-06-1501Search in Google Scholar PubMed
Kim, S., Bell, K., Mousa, S.A., and Varner, J.A. (2000). Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am. J. Pathol. 156, 1345–1362.10.1016/S0002-9440(10)65005-5Search in Google Scholar PubMed
Kim, J., Gao, P., Liu, Y.-C., Semenza, G.L., and Dang, C.V. (2007). Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27, 7381–7393.10.1128/MCB.00440-07Search in Google Scholar PubMed PubMed Central
Kolev, Y., Uetake, H., Takagi, Y., and Sugihara, K. (2008). Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1α) pathway, angiogenic factors production and poor prognosis. Ann. Surg. Oncol. 15, 2336–2344.10.1245/s10434-008-9955-5Search in Google Scholar PubMed
Kondoh, H., Lleonart, M.E., Gil, J., Wang, J., Degan, P., Peters, G., Martinez, D., Carnero, A., and Beach, D. (2005). Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185.10.1158/0008-5472.177.65.1Search in Google Scholar PubMed
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Bougioukas, G., Didilis, V., Gatter, K.C., Harris, A.L., and Tumour and Angiogenesis Research Group. (2003). Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br. J. Cancer 89, 877–885.10.1038/sj.bjc.6601205Search in Google Scholar PubMed PubMed Central
Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Gatter, K.C., Trarbach, T., Folprecht, G., Shi, M.M., Lebwohl, D., Jalava, T., Laurent, D., et al. (2011). Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy. Clin. Cancer Res. 17, 4892–4900.10.1158/1078-0432.CCR-10-2918Search in Google Scholar PubMed PubMed Central
Kozak, K.R., Abbott, B., and Hankinson, O. (1997). ARNT-deficient mice and placental differentiation. Dev. Biol. 191, 297–305.10.1006/dbio.1997.8758Search in Google Scholar PubMed
Kumar, V.B.S., Viji, R.I., Kiran, M.S., and Sudhakaran, P.R. (2007). Endothelial cell response to lactate: implication of PAR modification of VEGF. J. Cell. Physiol. 211, 477–485.10.1002/jcp.20955Search in Google Scholar PubMed
Lakka, S.S., Gondi, C.S., and Rao, J.S. (2005). Proteases and glioma angiogenesis. Brain Pathol. (Zurich) 15, 327–341.10.1111/j.1750-3639.2005.tb00118.xSearch in Google Scholar PubMed PubMed Central
Land, S.C. and Tee, A.R. (2007). Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 282, 20534–20543.10.1074/jbc.M611782200Search in Google Scholar PubMed
Laplante, M. and Sabatini, D.M. (2012). mTOR signaling in growth control and disease. Cell 149, 274–293.10.1016/j.cell.2012.03.017Search in Google Scholar PubMed PubMed Central
Le Sage, V., Cinti, A., Amorim, R., and Mouland, A.J. (2016). Adapting the stress response: viral subversion of the mTOR signaling pathway. Viruses 8, 152.10.3390/v8060152Search in Google Scholar PubMed PubMed Central
Lewis, B.C., Shim, H., Li, Q., Wu, C.S., Lee, L.A., Maity, A., and Dang, C.V. (1997). Identification of putative c-Myc-responsive genes: characterization of rcl, a novel growth-related gene. Mol. Cell. Biol. 17, 4967–4978.10.1128/MCB.17.9.4967Search in Google Scholar PubMed PubMed Central
Lewis, C.E., De Palma, M., and Naldini, L. (2007). Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 67, 8429–8432.10.1158/0008-5472.CAN-07-1684Search in Google Scholar PubMed
Li, G.-H., Wei, H., Lv, S.-Q., Ji, H., and Wang, D.-L. (2010). Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. Int. J. Oncol. 37, 103–110.Search in Google Scholar PubMed
Lian, X., Bao, X., Al-Ahmad, A., Liu, J., Wu, Y., Dong, W., Dunn, K.K., Shusta, E.V., and Palecek, S.P. (2014). Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of Wnt signaling. Stem Cell Rep. 3, 804–816.10.1016/j.stemcr.2014.09.005Search in Google Scholar PubMed PubMed Central
Lin, T.S., Mahajan, S., and Frank, D.A. (2000). STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19, 2496–2504.10.1038/sj.onc.1203486Search in Google Scholar PubMed
Lindahl, P., Johansson, B.R., Levéen, P., and Betsholtz, C. (1997). Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245.10.1126/science.277.5323.242Search in Google Scholar PubMed
Liu, C., Tu, Y., Sun, X., Jiang, J., Jin, X., Bo, X., Li, Z., Bian, A., Wang, X., Liu, D., et al. (2011a). Wnt/β-catenin pathway in human glioma: expression pattern and clinical/prognostic correlations. Clin. Exp. Med. 11, 105–112.10.1007/s10238-010-0110-9Search in Google Scholar PubMed
Liu, X., Wang, L., Zhao, S., Ji, X., Luo, Y., and Ling, F. (2011b). β-Catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastoma cells. Med. Oncol. Northwood (Lond.) 28, 608–614.10.1007/s12032-010-9476-5Search in Google Scholar PubMed
Liu, X., Zhang, Q., Mu, Y., Zhang, X., Sai, K., Pang, J.C.-S., Ng, H.K., and Chen, Z.P. (2011c). Clinical significance of vasculogenic mimicry in human gliomas. J. Neurooncol. 105, 173–179.10.1007/s11060-011-0578-5Search in Google Scholar PubMed PubMed Central
Liu, Y., Yan, W., Zhang, W., Chen, L., You, G., Bao, Z., Wang, Y., Wang, H., Kang, C., and Jiang, T. (2012). MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol. Rep. 28, 1013–1021.10.3892/or.2012.1902Search in Google Scholar PubMed
Loewith, R. and Hall, M.N. (2011). Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189, 1177–1201.10.1534/genetics.111.133363Search in Google Scholar PubMed PubMed Central
Louis, D.N. (2006). Molecular pathology of malignant gliomas. Annu. Rev. Pathol. 1, 97–117.10.1146/annurev.pathol.1.110304.100043Search in Google Scholar PubMed
Louis, D.N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W.K., Ohgaki, H., Wiestler, O.D., Kleihues, P., and Ellison, D.W. (2016). The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. (Berl.) 131, 803–820.10.1007/s00401-016-1545-1Search in Google Scholar PubMed
Lu, H., Forbes, R.A., and Verma, A. (2002). Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277, 23111–23115.10.1074/jbc.M202487200Search in Google Scholar PubMed
Lu, H., Dalgard, C.L., Mohyeldin, A., McFate, T., Tait, A.S., and Verma, A. (2005). Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem. 280, 41928–41939.10.1074/jbc.M508718200Search in Google Scholar PubMed
Lu, R., Jiang, M., Chen, Z., Xu, X., Hu, H., Zhao, X., Gao, X., and Guo, L. (2013). Lactate dehydrogenase 5 expression in non-Hodgkin lymphoma is associated with the induced hypoxia regulated protein and poor prognosis. PLoS One 8, e74853.10.1371/journal.pone.0074853Search in Google Scholar PubMed PubMed Central
Lum, J.J., Bui, T., Gruber, M., Gordan, J.D., DeBerardinis, R.J., Covello, K.L., Simon, M.C., and Thompson, C.B. (2007). The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 21, 1037–1049.10.1101/gad.1529107Search in Google Scholar PubMed PubMed Central
Luo, W. and Semenza, G.L. (2011). Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2, 551–556.10.18632/oncotarget.299Search in Google Scholar PubMed PubMed Central
Lv, L., Li, D., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., et al. (2011). Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730.10.1016/j.molcel.2011.04.025Search in Google Scholar PubMed PubMed Central
Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., Chadburn, A., Heissig, B., Marks, W., Witte, L., et al. (2001). Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194–1201.10.1038/nm1101-1194Search in Google Scholar PubMed
Ma, J., Meng, Y., Kwiatkowski, D.J., Chen, X., Peng, H., Sun, Q., Zha, X., Wang, F., Wang, Y., Jing, Y., et al. (2010). Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J. Clin. Invest. 120, 103–114.10.1172/JCI37964Search in Google Scholar PubMed PubMed Central
Machein, M.R., Renninger, S., de Lima-Hahn, E., and Plate, K.H. (2003). Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol. (Zurich) 13, 582–597.10.1111/j.1750-3639.2003.tb00487.xSearch in Google Scholar PubMed PubMed Central
Maisonpierre, P.C., Suri, C., Jones, P.F., Bartunkova, S., Wiegand, S.J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T.H., Papadopoulos, N., et al. (1997). Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60.10.1126/science.277.5322.55Search in Google Scholar PubMed
Mamelak, A.N. and Jacoby, D.B. (2007). Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601). Expert Opin. Drug Deliv. 4, 175–186.10.1517/17425247.4.2.175Search in Google Scholar PubMed
Mani, N., Khaibullina, A., Krum, J.M., and Rosenstein, J.M. (2003). Activation of receptor-mediated angiogenesis and signaling pathways after VEGF administration in fetal rat CNS explants. J. Cereb. Blood Flow Metab. 23, 1420–1429.10.1097/01.WCB.0000090620.86921.9CSearch in Google Scholar PubMed
Manning, B.D. and Cantley, L.C. (2007). AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274.10.1016/j.cell.2007.06.009Search in Google Scholar PubMed PubMed Central
Mao, H., Lebrun, D.G., Yang, J., Zhu, V.F., and Li, M. (2012). Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest. 30, 48–56.10.3109/07357907.2011.630050Search in Google Scholar PubMed PubMed Central
Marchetti, B. and Pluchino, S. (2013). Wnt your brain be inflamed? Yes, it Wnt! Trends Mol. Med. 19, 144–156.10.1016/j.molmed.2012.12.001Search in Google Scholar PubMed PubMed Central
Mathupala, S.P., Rempel, A., and Pedersen, P.L. (2001). Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J. Biol. Chem. 276, 43407–43412.10.1074/jbc.M108181200Search in Google Scholar PubMed
Maurer, G.D., Brucker, D.P., Bähr, O., Harter, P.N., Hattingen, E., Walenta, S., Mueller-Klieser, W., Steinbach, J.P., and Rieger, J. (2011). Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer 11, 315.10.1186/1471-2407-11-315Search in Google Scholar PubMed PubMed Central
Mazurek, S. (2011). Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol. 43, 969–980.10.1016/j.biocel.2010.02.005Search in Google Scholar PubMed
Mazzone, M., Selfors, L.M., Albeck, J., Overholtzer, M., Sale, S., Carroll, D.L., Pandya, D., Lu, Y., Mills, G.B., Aster, J.C., et al. (2010). Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc. Natl. Acad. Sci. USA 107, 5012–5017.10.1073/pnas.1000896107Search in Google Scholar PubMed PubMed Central
McEwen, B.S. and Reagan, L.P. (2004). Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur. J. Pharmacol. 490, 13–24.10.1016/j.ejphar.2004.02.041Search in Google Scholar PubMed
McFate, T., Mohyeldin, A., Lu, H., Thakar, J., Henriques, J., Halim, N.D., Wu, H., Schell, M.J., Tsang, T.M., Teahan, O., et al. (2008). Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J. Biol. Chem. 283, 22700–22708.10.1074/jbc.M801765200Search in Google Scholar PubMed PubMed Central
Mekhail, K., Khacho, M., Carrigan, A., Hache, R.R.J., Gunaratnam, L., and Lee, S. (2005). Regulation of ubiquitin ligase dynamics by the nucleolus. J. Cell Biol. 170, 733–744.10.1083/jcb.200506030Search in Google Scholar PubMed PubMed Central
Mellinghoff, I.K., Wang, M.Y., Vivanco, I., Haas-Kogan, D.A., Zhu, S., Dia, E.Q., Lu, K.V., Yoshimoto, K., Huang, J.H., Chute, D.J., et al. (2005). Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024.10.1056/NEJMoa051918Search in Google Scholar PubMed
Michalak, K.P., Maćkowska-Kędziora, A., Sobolewski, B., and Woźniak, P. (2015). Key roles of glutamine pathways in reprogramming the cancer metabolism. Oxid. Med. Cell. Longev. 2015, 964321.10.1155/2015/964321Search in Google Scholar PubMed PubMed Central
Michelakis, E.D., Webster, L., and Mackey, J.R. (2008). Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989–994.10.1038/sj.bjc.6604554Search in Google Scholar PubMed PubMed Central
Michelakis, E.D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E., Maguire, C., Gammer, T.L., Mackey, J.R., Fulton, D., et al. (2010). Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34.10.1126/scitranslmed.3000677Search in Google Scholar PubMed
Milovanova, T.N., Bhopale, V.M., Sorokina, E.M., Moore, J.S., Hunt, T.K., Hauer-Jensen, M., Velazquez, O.C., and Thom, S.R. (2008). Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1. Mol. Cell. Biol. 28, 6248–6261.10.1128/MCB.00795-08Search in Google Scholar PubMed PubMed Central
Mineura, K., Yasuda, T., Kowada, M., Shishido, F., Ogawa, T., and Uemura, K. (1986). Positron emission tomographic evaluation of histological malignancy in gliomas using oxygen-15 and fluorine-18-fluorodeoxyglucose. Neurol. Res. 8, 164–168.10.1080/01616412.1986.11739749Search in Google Scholar PubMed
Moon, R.T., Bowerman, B., Boutros, M., and Perrimon, N. (2002). The promise and perils of Wnt signaling through β-catenin. Science 296, 1644–1646.10.1126/science.1071549Search in Google Scholar PubMed
Moon, J.-H., Kwon, S., Jun, E.K., Kim, A., Whang, K.Y., Kim, H., Oh, S., Yoon, B.S., and You, S. (2011). Nanog-induced dedifferentiation of p53-deficient mouse astrocytes into brain cancer stem-like cells. Biochem. Biophys. Res. Commun. 412, 175–181.10.1016/j.bbrc.2011.07.070Search in Google Scholar PubMed
Mora, A., Komander, D., van Aalten, D.M.F., and Alessi, D.R. (2004). PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161–170.10.1016/j.semcdb.2003.12.022Search in Google Scholar PubMed
Mukherjee, J., Phillips, J.J., Zheng, S., Wiencke, J., Ronen, S.M., and Pieper, R.O. (2013). Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma. PLoS One 8, e57610.10.1371/journal.pone.0057610Search in Google Scholar PubMed PubMed Central
Murphy, J.F., Lennon, F., Steele, C., Kelleher, D., Fitzgerald, D., and Long, A.C. (2005). Engagement of CD44 modulates cyclooxygenase induction, VEGF generation, and proliferation in human vascular endothelial cells. FASEB J. 19, 446–448.10.1096/fj.03-1376fjeSearch in Google Scholar PubMed
Nager, M., Bhardwaj, D., Cantí, C., Medina, L., Nogués, P., and Herreros, J. (2012). β-Catenin signalling in glioblastoma multiforme and glioma-initiating cells. Chemother. Res. Pract. 2012, 192362.10.1155/2012/192362Search in Google Scholar PubMed PubMed Central
Nusse, R. (2005). Wnt signaling in disease and in development. Cell Res. 15, 28–32.10.1038/sj.cr.7290260Search in Google Scholar PubMed
Ohgaki, H., Dessen, P., Jourde, B., Horstmann, S., Nishikawa, T., Di Patre, P.-L., Burkhard, C., Schüler, D., Probst-Hensch, N.M., Maiorka, P.C., et al. (2004). Genetic pathways to glioblastoma: a population-based study. Cancer Res. 64, 6892–6899.10.1158/0008-5472.CAN-04-1337Search in Google Scholar PubMed
Ohno-Nakahara, M., Honda, K., Tanimoto, K., Tanaka, N., Doi, T., Suzuki, A., Yoneno, K., Nakatani, Y., Ueki, M., Ohno, S., et al. (2004). Induction of CD44 and MMP expression by hyaluronidase treatment of articular chondrocytes. J. Biochem. (Tokyo) 135, 567–575.10.1093/jb/mvh069Search in Google Scholar PubMed
Oliva, C.A., Vargas, J.Y., and Inestrosa, N.C. (2013). Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. Front. Cell. Neurosci. 7, 224.10.3389/fncel.2013.00224Search in Google Scholar PubMed PubMed Central
Onishi, M., Ichikawa, T., Kurozumi, K., and Date, I. (2011). Angiogenesis and invasion in glioma. Brain Tumor Pathol. 28, 13–24.10.1007/s10014-010-0007-zSearch in Google Scholar PubMed
Oudard, S., Arvelo, F., Miccoli, L., Apiou, F., Dutrillaux, A.M., Poisson, M., Dutrillaux, B., and Poupon, M.F. (1996). High glycolysis in gliomas despite low hexokinase transcription and activity correlated to chromosome 10 loss. Br. J. Cancer 74, 839–845.10.1038/bjc.1996.446Search in Google Scholar PubMed PubMed Central
Pardue, E.L., Ibrahim, S., and Ramamurthi, A. (2008). Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis 4, 203–214.10.4161/org.4.4.6926Search in Google Scholar PubMed PubMed Central
Park, K.S., Lee, R.D., Kang, S.-K., Han, S.Y., Park, K.L., Yang, K.H., Song, Y.S., Park, H.J., Lee, Y.M., Yun, Y.P., et al. (2004). Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-g via the JNK-dependent pathway. Exp. Cell Res. 297, 424–433.10.1016/j.yexcr.2004.03.034Search in Google Scholar PubMed
Parliament, M.B., Allalunis-Turner, M.J., Franko, A.J., Olive, P.L., Mandyam, R., Santos, C., and Wolokoff, B. (2000). Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours. Br. J. Cancer 82, 635–641.10.1054/bjoc.1999.0975Search in Google Scholar PubMed PubMed Central
Pate, K.T., Stringari, C., Sprowl-Tanio, S., Wang, K., TeSlaa, T., Hoverter, N.P., McQuade, M.M., Garner, C., Digman, M.A., Teitell, M.A., et al. (2014). Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 33, 1454–1473.10.15252/embj.201488598Search in Google Scholar PubMed PubMed Central
Patenaude, A., Parker, J., and Karsan, A. (2010). Involvement of endothelial progenitor cells in tumor vascularization. Microvasc. Res. 79, 217–223.10.1016/j.mvr.2010.01.007Search in Google Scholar PubMed
Patil, S.A., Hosni-Ahmed, A., Jones, T.S., Patil, R., Pfeffer, L.M., and Miller, D.D. (2013). Novel approaches to glioma drug design and drug screening. Expert Opin. Drug Discov. 8, 1135–1151.10.1517/17460441.2013.807248Search in Google Scholar PubMed
Paw, I., Carpenter, R.C., Watabe, K., Debinski, W., and Lo, H.-W. (2015). Mechanisms regulating glioma invasion. Cancer Lett. 362, 1–7.10.1016/j.canlet.2015.03.015Search in Google Scholar PubMed PubMed Central
Pearson, H. (2007). Cancer patients opt for unapproved drug. Nature 446, 474–475.10.1038/446474aSearch in Google Scholar PubMed
Pereira, K.M.A., Chaves, F.N., Viana, T.S.A., Carvalho, F.S.R., Costa, F.W.G., Alves, A.P.N.N., Negreiros Nunes Alves¸ A.P., and Sousa, F.B. (2013). Oxygen metabolism in oral cancer: HIF and GLUTs. Oncol. Lett. 6, 311–316.10.3892/ol.2013.1371Search in Google Scholar PubMed PubMed Central
Plate, K.H., Breier, G., Weich, H.A., and Risau, W. (1992). Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848.10.1038/359845a0Search in Google Scholar PubMed
Plate, K.H., Breier, G., Weich, H.A., Mennel, H.D., and Risau, W. (1994). Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int. J. Cancer 59, 520–529.10.1002/ijc.2910590415Search in Google Scholar PubMed
Plate, K.H., Scholz, A., and Dumont, D.J. (2012). Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol. (Berl.) 124, 763–775.10.1007/s00401-012-1066-5Search in Google Scholar PubMed PubMed Central
Polet, F. and Feron, O. (2013). Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. J. Intern. Med. 273, 156–165.10.1111/joim.12016Search in Google Scholar PubMed
Popescu, A.M., Purcaru, S.O., Alexandru, O., and Dricu, A. (2016). New perspectives in glioblastoma antiangiogenic therapy. Contemp. Oncol. Poznan Pol. 20, 109–118.10.5114/wo.2015.56122Search in Google Scholar
Porporato, P.E., Payen, V.L., De Saedeleer, C.J., Préat, V., Thissen, J.-P., Feron, O., and Sonveaux, P. (2012). Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15, 581–592.10.1007/s10456-012-9282-0Search in Google Scholar PubMed
Pu, P., Zhang, Z., Kang, C., Jiang, R., Jia, Z., Wang, G., and Jiang, H. (2009). Downregulation of Wnt2 and β-catenin by siRNA suppresses malignant glioma cell growth. Cancer Gene Ther. 16, 351–361.10.1038/cgt.2008.78Search in Google Scholar PubMed
Pugh, C.W. and Ratcliffe, P.J. (2003). Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 9, 677–684.10.1038/nm0603-677Search in Google Scholar PubMed
Pulselli, R., Amadio, L., Fanciulli, M., and Floridi, A. (1996). Effect of lonidamine on the mitochondrial potential in situ in Ehrlich ascites tumor cells. Anticancer Res. 16, 419–423.Search in Google Scholar PubMed
Rafii, S. and Lyden, D. (2008). Cancer. A few to flip the angiogenic switch. Science 319, 163–164.10.1126/science.1153615Search in Google Scholar
Raghunand, N., Gatenby, R.A., and Gillies, R.J. (2003). Microenvironmental and cellular consequences of altered blood flow in tumours. Br. J. Radiol. 76 Spec No. 1, S11–S22.10.1259/bjr/12913493Search in Google Scholar
Rapisarda, A. and Melillo, G. (2012). Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat. Rev. Clin. Oncol. 9, 378–390.10.1038/nrclinonc.2012.64Search in Google Scholar PubMed
Reiss, Y., Machein, M.R., and Plate, K.H. (2005). The role of angiopoietins during angiogenesis in gliomas. Brain Pathol. (Zurich) 15, 311–317.10.1111/j.1750-3639.2005.tb00116.xSearch in Google Scholar
Ricard, D., Idbaih, A., Ducray, F., Lahutte, M., Hoang-Xuan, K., and Delattre, J.-Y. (2012). Primary brain tumours in adults. Lancet 379, 1984–1996.10.1016/S0140-6736(11)61346-9Search in Google Scholar PubMed
Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., Maira, G., Parati, E.A., Stassi, G., Larocca, L.M., et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828.10.1038/nature09557Search in Google Scholar PubMed
Risau, W. (1997). Mechanisms of angiogenesis. Nature 386, 671–674.10.1038/386671a0Search in Google Scholar PubMed
Risau, W. and Flamme, I. (1995). Vasculogenesis. Annu. Rev. Cell Dev. Biol. 11, 73–91.10.1146/annurev.cb.11.110195.000445Search in Google Scholar PubMed
Roche, T.E., Baker, J.C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., Dong, J., Turkan, A., and Kasten, S.A. (2001). Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Prog. Nucleic Acid Res. Mol. Biol. 70, 33–75.10.1016/S0079-6603(01)70013-XSearch in Google Scholar PubMed
Rodgers, L.S., Lalani, S., Hardy, K.M., Xiang, X., Broka, D., Antin, P.B., and Camenisch, T.D. (2006). Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation. Circ. Res. 99, 583–589.10.1161/01.RES.0000242561.95978.43Search in Google Scholar PubMed
Rooprai, H.K. and McCormick, D. (1997). Proteases and their inhibitors in human brain tumours: a review. Anticancer Res. 17, 4151–4162.Search in Google Scholar PubMed
Rossi, M., Magnoni, L., Miracco, C., Mori, E., Tosi, P., Pirtoli, L., Tini, P., Oliveri, G., Cosci, E., and Bakker, A. (2011). β-Catenin and Gli1 are prognostic markers in glioblastoma. Cancer Biol. Ther. 11, 753–761.10.4161/cbt.11.8.14894Search in Google Scholar PubMed
Ruzinova, M.B., Schoer, R.A., Gerald, W., Egan, J.E., Pandolfi, P.P., Rafii, S., Manova, K., Mittal, V., and Benezra, R. (2003). Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell 4, 277–289.10.1016/S1535-6108(03)00240-XSearch in Google Scholar PubMed
Ryo, A., Nakamura, M., Wulf, G., Liou, Y.C., and Lu, K.P. (2001). Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nat. Cell Biol. 3, 793–801.10.1038/ncb0901-793Search in Google Scholar PubMed
Safran, M. and Kaelin, W.G. (2003). HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest. 111, 779–783.10.1172/JCI200318181Search in Google Scholar PubMed
Salinas, P.C. (2012). Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function. Cold Spring Harb. Perspect. Biol. 4, a008003.10.1101/cshperspect.a008003Search in Google Scholar PubMed PubMed Central
Sami, A. and Karsy, M. (2013). Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 34, 1991–2002.10.1007/s13277-013-0800-5Search in Google Scholar PubMed
San-Millán, I. and Brooks, G.A. (2016). Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis 38, 119–133.10.1093/carcin/bgw127Search in Google Scholar PubMed PubMed Central
Sanzey, M., Abdul Rahim, S.A., Oudin, A., Dirkse, A., Kaoma, T., Vallar, L., Herold-Mende, C., Bjerkvig, R., Golebiewska, A., and Niclou, S.P. (2015). Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. PLoS One 10, e0123544.10.1371/journal.pone.0123544Search in Google Scholar PubMed PubMed Central
Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101.10.1126/science.1106148Search in Google Scholar PubMed
Sareddy, G.R., Panigrahi, M., Challa, S., Mahadevan, A., and Babu, P.P. (2009). Activation of Wnt/β-catenin/Tcf signaling pathway in human astrocytomas. Neurochem. Int. 55, 307–317.10.1016/j.neuint.2009.03.016Search in Google Scholar PubMed
Sato, T., Nakashima, A., Guo, L., and Tamanoi, F. (2009). Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem. 284, 12783–12791.10.1074/jbc.M809207200Search in Google Scholar PubMed PubMed Central
Sattler, U.G.A., Meyer, S.S., Quennet, V., Hoerner, C., Knoerzer, H., Fabian, C., Yaromina, A., Zips, D., Walenta, S., Baumann, M., et al. (2010). Glycolytic metabolism and tumour response to fractionated irradiation. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 94, 102–109.10.1016/j.radonc.2009.11.007Search in Google Scholar PubMed
Schaefer, L.K., Ren, Z., Fuller, G.N., and Schaefer, T.S. (2002). Constitutive activation of Stat3a in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21, 2058–2065.10.1038/sj.onc.1205263Search in Google Scholar PubMed
Schoenfelder, M. and Einspanier, R. (2003). Expression of hyaluronan synthases and corresponding hyaluronan receptors is differentially regulated during oocyte maturation in cattle. Biol. Reprod. 69, 269–277.10.1095/biolreprod.102.011577Search in Google Scholar PubMed
Schubert, D. (2005). Glucose metabolism and Alzheimer’s disease. Ageing Res. Rev. 4, 240–257.10.1016/j.arr.2005.02.003Search in Google Scholar PubMed
Seliger, C., Leukel, P., Moeckel, S., Jachnik, B., Lottaz, C., Kreutz, M., Brawanski, A., Proescholdt, M., Bogdahn, U., Bosserhoff, A.-K., et al. (2013). Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-β2 and migration of glioma cells in vitro. PLoS One 8, e78935.10.1371/journal.pone.0078935Search in Google Scholar PubMed PubMed Central
Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732.10.1038/nrc1187Search in Google Scholar PubMed
Semenza, G.L. (2010a). Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634.10.1038/onc.2009.441Search in Google Scholar PubMed PubMed Central
Semenza, G.L. (2010b). HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56.10.1016/j.gde.2009.10.009Search in Google Scholar PubMed PubMed Central
Semenza, G.L. (2012). Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33, 207–214.10.1016/j.tips.2012.01.005Search in Google Scholar PubMed PubMed Central
Semenza, G.L. (2014). Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 76, 39–56.10.1146/annurev-physiol-021113-170322Search in Google Scholar PubMed PubMed Central
Semenza, G.L., Jiang, B.H., Leung, S.W., Passantino, R., Concordet, J.P., Maire, P., and Giallongo, A. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537.10.1074/jbc.271.51.32529Search in Google Scholar PubMed
Seshacharyulu, P., Ponnusamy, M.P., Haridas, D., Jain, M., Ganti, A.K., and Batra, S.K. (2012). Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16, 15–31.10.1517/14728222.2011.648617Search in Google Scholar PubMed PubMed Central
Shanmugasundaram, K., Block, K., Nayak, B.K., Livi, C.B., Venkatachalam, M.A., and Sudarshan, S. (2013). PI3K regulation of the SKP-2/p27 axis through mTORC2. Oncogene 32, 2027–2036.10.1038/onc.2012.226Search in Google Scholar PubMed PubMed Central
Shaw, R.J. (2006). Glucose metabolism and cancer. Curr. Opin. Cell Biol. 18, 598–608.10.1016/j.ceb.2006.10.005Search in Google Scholar PubMed
Sherry, M.M., Reeves, A., Wu, J.K., and Cochran, B.H. (2009). STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27, 2383–2392.10.1002/stem.185Search in Google Scholar PubMed PubMed Central
Shi, Q., Le, X., Wang, B., Abbruzzese, J.L., Xiong, Q., He, Y., and Xie, K. (2001). Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20, 3751–3756.10.1038/sj.onc.1204500Search in Google Scholar PubMed
Shi, Z., Qian, X., Li, L., Zhang, J., Zhu, S., Zhu, J., Chen, L., Zhang, K., Han, L., Yu, S., et al. (2012). Nuclear translocation of β-catenin is essential for glioma cell survival. J. Neuroimmune Pharmacol. 7, 892–903.10.1007/s11481-012-9354-3Search in Google Scholar PubMed
Shibuya, K., Okada, M., Suzuki, S., Seino, M., Seino, S., Takeda, H., and Kitanaka, C. (2015). Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells. Oncotarget 6, 651–661.10.18632/oncotarget.2892Search in Google Scholar PubMed PubMed Central
Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., Dalla-Favera, R., and Dang, C.V. (1997). c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. USA 94, 6658–6663.10.1073/pnas.94.13.6658Search in Google Scholar PubMed PubMed Central
Shtutman, M., Zhurinsky, J., Simcha, I., Albanese, C., D’Amico, M., Pestell, R., and Ben-Ze’ev, A. (1999). The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc. Natl. Acad. Sci. USA 96, 5522–5527.10.1073/pnas.96.10.5522Search in Google Scholar PubMed PubMed Central
Sinibaldi, D., Wharton, W., Turkson, J., Bowman, T., Pledger, W.J., and Jove, R. (2000). Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. Oncogene 19, 5419–5427.10.1038/sj.onc.1203947Search in Google Scholar PubMed
Song, J.I. and Grandis, J.R. (2000). STAT signaling in head and neck cancer. Oncogene 19, 2489–2495.10.1038/sj.onc.1203483Search in Google Scholar PubMed
Sonveaux, P., Copetti, T., De Saedeleer, C.J., Végran, F., Verrax, J., Kennedy, K.M., Moon, E.J., Dhup, S., Danhier, P., Frérart, F., et al. (2012). Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 7, e33418.10.1371/journal.pone.0033418Search in Google Scholar PubMed PubMed Central
Spring, H., Schüler, T., Arnold, B., Hämmerling, G.J., and Ganss, R. (2005). Chemokines direct endothelial progenitors into tumor neovessels. Proc. Natl. Acad. Sci. USA 102, 18111–18116.10.1073/pnas.0507158102Search in Google Scholar PubMed PubMed Central
Stacpoole, P.W., Nagaraja, N.V., and Hutson, A.D. (2003). Efficacy of dichloroacetate as a lactate-lowering drug. J. Clin. Pharmacol. 43, 683–691.10.1177/0091270003254637Search in Google Scholar PubMed
Stenman, J.M., Rajagopal, J., Carroll, T.J., Ishibashi, M., McMahon, J., and McMahon, A.P. (2008). Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250.10.1126/science.1164594Search in Google Scholar PubMed
Stern, R. (2008). Hyaluronidases in cancer biology. Semin. Cancer Biol. 18, 275–280.10.1016/j.semcancer.2008.03.017Search in Google Scholar PubMed
Stern, R., Shuster, S., Neudecker, B.A., and Formby, B. (2002). Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp. Cell Res. 276, 24–31.10.1006/excr.2002.5508Search in Google Scholar PubMed
Stratmann, A., Risau, W., and Plate, K.H. (1998). Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. J. Pathol. 153, 1459–1466.10.1016/S0002-9440(10)65733-1Search in Google Scholar PubMed
Strickland, M. and Stoll, E.A. (2017). Metabolic reprogramming in glioma. Front. Cell Dev. Biol. 5, 43.10.3389/fcell.2017.00043Search in Google Scholar PubMed PubMed Central
Sturgeon, C.M., Ditadi, A., Awong, G., Kennedy, M., and Keller, G. (2014). Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat. Biotechnol. 32, 554–561.10.1038/nbt.2915Search in Google Scholar PubMed PubMed Central
Sun, Q., Chen, X., Ma, J., Peng, H., Wang, F., Zha, X., Wang, Y., Jing, Y., Yang, H., Chen, R., et al. (2011). Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc. Natl. Acad. Sci. USA 108, 4129–4134.10.1073/pnas.1014769108Search in Google Scholar PubMed PubMed Central
Sutendra, G., Dromparis, P., Kinnaird, A., Stenson, T.H., Haromy, A., Parker, J.M.R., McMurtry, M.S., and Michelakis, E.D. (2013). Mitochondrial activation by inhibition of PDKII suppresses HIF1α signaling and angiogenesis in cancer. Oncogene 32, 1638–1650.10.1038/onc.2012.198Search in Google Scholar PubMed
Tabancay, A.P., Gau, C.-L., Machado, I.M.P., Uhlmann, E.J., Gutmann, D.H., Guo, L., and Tamanoi, F. (2003). Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278, 39921–39930.10.1074/jbc.M306553200Search in Google Scholar PubMed
Tan, X., Apte, U., Micsenyi, A., Kotsagrelos, E., Luo, J.-H., Ranganathan, S., Monga, D.K., Bell, A., Michalopoulos, G.K., and Monga, S.P. (2005). Epidermal growth factor receptor: a novel target of the Wnt/β-catenin pathway in liver. Gastroenterology 129, 285–302.10.1053/j.gastro.2005.04.013Search in Google Scholar PubMed PubMed Central
Tee, A.R., Blenis, J., and Proud, C.G. (2005). Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett. 579, 4763–4768.10.1016/j.febslet.2005.07.054Search in Google Scholar PubMed
Thompson, C.B. (2014). Wnt meets Warburg: another piece in the puzzle? EMBO J. 33, 1420–1422.10.15252/embj.201488785Search in Google Scholar PubMed PubMed Central
Toschi, A., Lee, E., Gadir, N., Ohh, M., and Foster, D.A. (2008). Differential dependence of hypoxia-inducible factors 1α and 2α on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495–34499.10.1074/jbc.C800170200Search in Google Scholar PubMed PubMed Central
Trabold, O., Wagner, S., Wicke, C., Scheuenstuhl, H., Hussain, M.Z., Rosen, N., Seremetiev, A., Becker, H.D., and Hunt, T.K. (2003). Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 11, 504–509.10.1046/j.1524-475X.2003.11621.xSearch in Google Scholar PubMed
Tsacopoulos, M. and Magistretti, P.J. (1996). Metabolic coupling between glia and neurons. J. Neurosci. 16, 877–885.10.1523/JNEUROSCI.16-03-00877.1996Search in Google Scholar PubMed
Turner, D.A. and Adamson, D.C. (2011). Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism. J. Neuropathol. Exp. Neurol. 70, 167–176.10.1097/NEN.0b013e31820e1152Search in Google Scholar PubMed PubMed Central
Unruh, A., Ressel, A., Mohamed, H.G., Johnson, R.S., Nadrowitz, R., Richter, E., Katschinski, D.M., and Wenger, R.H. (2003). The hypoxia-inducible factor-1α is a negative factor for tumor therapy. Oncogene 22, 3213–3220.10.1038/sj.onc.1206385Search in Google Scholar PubMed
Unwin, R.D., Craven, R.A., Harnden, P., Hanrahan, S., Totty, N., Knowles, M., Eardley, I., Selby, P.J., and Banks, R.E. (2003). Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect. Proteomics 3, 1620–1632.10.1002/pmic.200300464Search in Google Scholar PubMed
Utsuki, S., Sato, Y., Oka, H., Tsuchiya, B., Suzuki, S., and Fujii, K. (2002). Relationship between the expression of E-, N-cadherins and β-catenin and tumor grade in astrocytomas. J. Neurooncol. 57, 187–192.10.1023/A:1015720220602Search in Google Scholar
Valvona, C.J., Fillmore, H.L., Nunn, P.B., and Pilkington, G.J. (2016). The regulation and function of lactate dehydrogenase A: therapeutic potential in brain tumor. Brain Pathol. (Zurich) 26, 3–17.10.1111/bpa.12299Search in Google Scholar PubMed PubMed Central
Vander Heiden, M.G. (2011). Targeting cancer metabolism: a therapeutic window opens. Nat. Rev. Drug Discov. 10, 671–684.10.1038/nrd3504Search in Google Scholar PubMed
Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033.10.1126/science.1160809Search in Google Scholar PubMed PubMed Central
Vanhaesebroeck, B., Stephens, L., and Hawkins, P. (2012). PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13, 195–203.10.1038/nrm3290Search in Google Scholar PubMed
Végran, F., Boidot, R., Michiels, C., Sonveaux, P., and Feron, O. (2011). Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550–2560.10.1158/0008-5472.CAN-10-2828Search in Google Scholar PubMed
Velpula, K.K., Bhasin, A., Asuthkar, S., and Tsung, A.J. (2013). Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. Cancer Res. 73, 7277–7289.10.1158/0008-5472.CAN-13-1868Search in Google Scholar PubMed
Venneri, M.A., De Palma, M., Ponzoni, M., Pucci, F., Scielzo, C., Zonari, E., Mazzieri, R., Doglioni, C., and Naldini, L. (2007). Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109, 5276–5285.10.1182/blood-2006-10-053504Search in Google Scholar PubMed
Venneti, S. and Thompson, C.B. (2017). Metabolic reprogramming in brain tumors. Annu. Rev. Pathol. 12, 515–545.10.1146/annurev-pathol-012615-044329Search in Google Scholar PubMed
Vogt, P.K. and Hart, J.R. (2011). PI3K and STAT3: a new alliance. Cancer Discov. 1, 481–486.10.1158/2159-8290.CD-11-0218Search in Google Scholar PubMed PubMed Central
Walenta, S. and Mueller-Klieser, W.F. (2004). Lactate: mirror and motor of tumor malignancy. Semin. Radiat. Oncol. 14, 267–274.10.1016/j.semradonc.2004.04.004Search in Google Scholar PubMed
Wan, Z., Shi, W., Shao, B., Shi, J., Shen, A., Ma, Y., Chen, J., and Lan, Q. (2011). Peroxisome proliferator-activated receptor γ agonist pioglitazone inhibits β-catenin-mediated glioma cell growth and invasion. Mol. Cell. Biochem. 349, 1–10.10.1007/s11010-010-0637-9Search in Google Scholar PubMed
Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K.E., Geber, A., Fligelman, B., Leversha, M., Brennan, C., and Tabar, V. (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833.10.1038/nature09624Search in Google Scholar PubMed
Wang, L., Chen, L., Wang, Q., Wang, L., Wang, H., Shen, Y., and Yu, Y. (2014). Circulating endothelial progenitor cells are involved in VEGFR-2-related endothelial differentiation in glioma. Oncol. Rep. 32, 2007–2014.10.3892/or.2014.3467Search in Google Scholar PubMed
Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.10.1126/science.123.3191.309Search in Google Scholar PubMed
West, D.C., Hampson, I.N., Arnold, F., and Kumar, S. (1985). Angiogenesis induced by degradation products of hyaluronic acid. Science 228, 1324–1326.10.1126/science.2408340Search in Google Scholar PubMed
Wike-Hooley, J.L., Haveman, J., and Reinhold, H.S. (1984). The relevance of tumour pH to the treatment of malignant disease. Radiother. Oncol. 2, 343–366.10.1016/S0167-8140(84)80077-8Search in Google Scholar PubMed
Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.-Y., Pfeiffer, H.K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S.B., et al. (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. USA 105, 18782–18787.10.1073/pnas.0810199105Search in Google Scholar PubMed PubMed Central
Wolf, A., Agnihotri, S., and Guha, A. (2010). Targeting metabolic remodeling in glioblastoma multiforme. Oncotarget 1, 552–562.10.18632/oncotarget.190Search in Google Scholar PubMed PubMed Central
Wolf, A., Agnihotri, S., Micallef, J., Mukherjee, J., Sabha, N., Cairns, R., Hawkins, C., and Guha, A. (2011). Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 208, 313–326.10.1084/jem.20101470Search in Google Scholar PubMed PubMed Central
Woll, P.S., Morris, J.K., Painschab, M.S., Marcus, R.K., Kohn, A.D., Biechele, T.L., Moon, R.T., and Kaufman, D.S. (2008). Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells. Blood 111, 122–131.10.1182/blood-2007-04-084186Search in Google Scholar PubMed PubMed Central
Wong, A.L., Haroon, Z.A., Werner, S., Dewhirst, M.W., Greenberg, C.S., and Peters, K.G. (1997). Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 81, 567–574.10.1161/01.RES.81.4.567Search in Google Scholar PubMed
Wu, D. and Pan, W. (2010). GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem. Sci. 35, 161–168.10.1016/j.tibs.2009.10.002Search in Google Scholar PubMed PubMed Central
Wu, J., Fang, J., Yang, Z., Chen, F., Liu, J., and Wang, Y. (2012). Wnt inhibitory factor-1 regulates glioblastoma cell cycle and proliferation. J. Clin. Neurosci. 19, 1428–1432.10.1016/j.jocn.2011.12.023Search in Google Scholar PubMed
Xu, L. and Fidler, I.J. (2000). Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res. 60, 4610–4616.Search in Google Scholar PubMed
Xu, L., Fukumura, D., and Jain, R.K. (2002). Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. J. Biol. Chem. 277, 11368–11374.10.1074/jbc.M108347200Search in Google Scholar PubMed
Xu, Q., Briggs, J., Park, S., Niu, G., Kortylewski, M., Zhang, S., Gritsko, T., Turkson, J., Kay, H., Semenza, G.L., et al. (2005). Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24, 5552–5560.10.1038/sj.onc.1208719Search in Google Scholar PubMed
Xu, C., Wang, J., Zhu, T., Shen, Y., Tang, X., Fang, L., and Xu, Y. (2016). Cross-talking between PPAR and Wnt signaling and its regulation in mesenchymal stem cell differentiation. Curr. Stem Cell Res. Ther. 11, 247–254.10.2174/1574888X10666150723145707Search in Google Scholar PubMed
Yan, S., Zhou, C., Zhang, W., Zhang, G., Zhao, X., Yang, S., Wang, Y., Lu, N., Zhu, H., and Xu, N. (2008). β-Catenin/TCF pathway upregulates STAT3 expression in human esophageal squamous cell carcinoma. Cancer Lett. 271, 85–97.10.1016/j.canlet.2008.05.035Search in Google Scholar PubMed
Yang, Z., Wang, Y., Fang, J., Chen, F., Liu, J., Wu, J., Wang, Y., Song, T., Zeng, F., and Rao, Y. (2010). Downregulation of WIF-1 by hypermethylation in astrocytomas. Acta Biochim. Biophys. Sin. 42, 418–425.10.1093/abbs/gmq037Search in Google Scholar PubMed
Yang, C., Iyer, R.R., Yu, A.C.H., Yong, R.L., Park, D.M., Weil, R.J., Ikejiri, B., Brady, R.O., Lonser, R.R., and Zhuang, Z. (2012a). β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas. Proc. Natl. Acad. Sci. USA 109, 6963–6968.10.1073/pnas.1118754109Search in Google Scholar PubMed PubMed Central
Yang, W., Xia, Y., Hawke, D., Li, X., Liang, J., Xing, D., Aldape, K., Hunter, T., Alfred Yung, W.K., and Lu, Z. (2012b). PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150, 685–696.10.1016/j.cell.2012.07.018Search in Google Scholar PubMed PubMed Central
Yang, W., Zheng, Y., Xia, Y., Ji, H., Chen, X., Guo, F., Lyssiotis, C.A., Aldape, K., Cantley, L.C., and Lu, Z. (2012c). ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol. 14, 1295–1304.10.1038/ncb2629Search in Google Scholar PubMed PubMed Central
Yang, J., Yang, Q., Yu, J., Li, X., Yu, S., and Zhang, X. (2016). SPOCK1 promotes the proliferation, migration and invasion of glioma cells through PI3K/AKT and Wnt/β-catenin signaling pathways. Oncol. Rep. 35, 3566–3576.10.3892/or.2016.4757Search in Google Scholar PubMed
Yeung, S.J., Pan, J., and Lee, M.-H. (2008). Roles of p53, MYC and HIF-1 in regulating glycolysis – the seventh hallmark of cancer. Cell. Mol. Life Sci. 65, 3981–3999.10.1007/s00018-008-8224-xSearch in Google Scholar PubMed
Yokoyama, T., Kondo, Y., and Kondo, S. (2007). Roles of mTOR and STAT3 in autophagy induced by telomere 3′ overhang-specific DNA oligonucleotides. Autophagy 3, 496–498.10.4161/auto.4602Search in Google Scholar PubMed
Yu, Q. and Stamenkovic, I. (2000). Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176.10.1101/gad.14.2.163Search in Google Scholar PubMed
Yu, J.M., Jun, E.S., Jung, J.S., Suh, S.Y., Han, J.Y., Kim, J.Y., and Jung, J.S. (2007). Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett. 257, 172–181.10.1016/j.canlet.2007.07.011Search in Google Scholar PubMed
Yu, L., Su, B., Hollomon, M., Deng, Y., Facchinetti, V., and Kleinerman, E.S. (2010). Vasculogenesis driven by bone marrow-derived cells is essential for growth of Ewing’s sarcomas. Cancer Res. 70, 1334–1343.10.1158/0008-5472.CAN-09-2795Search in Google Scholar PubMed PubMed Central
Yue, W.-Y. and Chen, Z.-P. (2005). Does vasculogenic mimicry exist in astrocytoma? J. Histochem. Cytochem. 53, 997–1002.10.1369/jhc.4A6521.2005Search in Google Scholar PubMed
Yue, X., Lan, F., Yang, W., Yang, Y., Han, L., Zhang, A., Liu, J., Zeng, H., Jiang, T., Pu, P., et al. (2010). Interruption of β-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells. Brain Res. 1366, 27–37.10.1016/j.brainres.2010.10.032Search in Google Scholar PubMed
Zadeh, G., Koushan, K., Pillo, L., Shannon, P., and Guha, A. (2004). Role of Ang1 and its interaction with VEGF-A in astrocytomas. J. Neuropathol. Exp. Neurol. 63, 978–989.10.1093/jnen/63.9.978Search in Google Scholar PubMed
Zagzag, D., Amirnovin, R., Greco, M.A., Yee, H., Holash, J., Wiegand, S.J., Zabski, S., Yancopoulos, G.D., and Grumet, M. (2000a). Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab. Investig. J. Tech. Methods Pathol. 80, 837–849.10.1038/labinvest.3780088Search in Google Scholar
Zagzag, D., Zhong, H., Scalzitti, J.M., Laughner, E., Simons, J.W., and Semenza, G.L. (2000b). Expression of hypoxia-inducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88, 2606–2618.10.1002/1097-0142(20000601)88:11<2606::AID-CNCR25>3.0.CO;2-WSearch in Google Scholar
Zhang, Y., Thant, A.A., Machida, K., Ichigotani, Y., Naito, Y., Hiraiwa, Y., Senga, T., Sohara, Y., Matsuda, S., and Hamaguchi, M. (2002). Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90. Cancer Res. 62, 3962–3965.Search in Google Scholar
Zhang, Z., Chen, H., Chen, Y., and Cheng, X. (2009). Significance of β-catenin and cyclin D1 express in glioma [in Chinese]. J. Cell. Mol. Immunol. 25, 1010–1012.Search in Google Scholar
Zhang, J., Huang, K., Shi, Z., Zou, J., Wang, Y., Jia, Z., Zhang, A., Han, L., Yue, X., Liu, N., et al. (2011). High β-catenin/Tcf-4 activity confers glioma progression via direct regulation of AKT2 gene expression. Neuro-Oncology 13, 600–609.10.1093/neuonc/nor034Search in Google Scholar PubMed
Zhang, T.-B., Zhao, Y., Tong, Z.-X., and Guan, Y.-F. (2015). Inhibition of glucose-transporter 1 (GLUT-1) expression reversed Warburg effect in gastric cancer cell MKN45. Int. J. Clin. Exp. Med. 8, 2423–2428.Search in Google Scholar PubMed
Zhao, P., Li, Q., Shi, Z., Li, C., Wang, L., Liu, X., Jiang, C., Qian, X., You, Y., Liu, N., et al. (2015). GSK-3β regulates tumor growth and angiogenesis in human glioma cells. Oncotarget 6, 31901–31915.10.18632/oncotarget.5043Search in Google Scholar PubMed
Zhu, Y. and Parada, L.F. (2002). The molecular and genetic basis of neurological tumours. Nat. Rev. Cancer 2, 616–626.10.1038/nrc866Search in Google Scholar PubMed
Zimna, A. and Kurpisz, M. (2015). Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. BioMed Res. Int. 2015, 549412.10.1155/2015/549412Search in Google Scholar PubMed
Zoncu, R., Efeyan, A., and Sabatini, D.M. (2011). mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35.10.1038/nrm3025Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston