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Autophagy, a double-edged sword in anti-angiogenesis therapy

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Abstract

Autophagy is a highly conservative cell behavior to keep the intracellular homeostasis and is frequently activated when cells encounter disgusting conditions, such as nutrition or growth factor deprive, hypoxia and cytotoxic agents. However, the precise role of autophagy under various conditions may be opposite, differ from protect cells survival to promote cells death, and the mechanism of this conditional-dependent role is still unclear. Anti-angiogenesis agents, such as bevacizumab, sorafenib and sunitinib, could reduce tumor microvascular density and increase tumor hypoxia, thus up-regulating autophagy activation of tumor cells, but the function of autophagy induced by anti-angiogenesis agents is still divergent and is considered to play a cytoprotective role in most cases. In this review, we mainly discuss the relationship between anti-angiogenesis therapy-induced hypoxia and autophagy, and pay special attention on the exact role of anti-angiogenesis agents induced autophagy in the process of anti-angiogenesis treatment.

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References

  1. Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  2. Wachsberger P, Burd R, Dicker AP. Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin Cancer Res. 2003;9(6):1957–71.

    CAS  PubMed  Google Scholar 

  3. Naito H, Takara K, Wakabayashi T, Kawahara H, Kidoya H, Takakura N. Changes in blood vessel maturation in the fibrous cap of the tumor rim. Cancer Sci. 2012;103(3):433–8.

    Article  CAS  PubMed  Google Scholar 

  4. Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res. 2007;74(2–3):72–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453(7193):410–4.

    Article  CAS  PubMed  Google Scholar 

  6. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann of Oncol. 2009;20(11):1842–7.

    Article  Google Scholar 

  7. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.

    Article  CAS  PubMed  Google Scholar 

  8. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22(11):2184–91.

    Article  CAS  PubMed  Google Scholar 

  9. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. New Engl J Med. 2007;357(26):2666–76.

    Article  CAS  PubMed  Google Scholar 

  10. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. New Engl J Med. 2003;349(5):427–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Investig. 2006;116(10):2610–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Yorimitsu T, Klionsky DJ. Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol. 2007;17(6):279–85.

    Article  CAS  PubMed  Google Scholar 

  13. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672–6.

    Article  CAS  PubMed  Google Scholar 

  15. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Investig. 2003;112(12):1809–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Marino G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, Lopez-Otin C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem. 2007;282(25):18573–83.

    Article  CAS  PubMed  Google Scholar 

  17. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21(13):1621–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Karantza-Wadsworth V, White E. Role of autophagy in breast cancer. Autophagy. 2007;3(6):610–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta. 2010;1806(2):220–9.

    CAS  PubMed  Google Scholar 

  20. Li YY, Lam SK, Mak JC, Zheng CY, Ho JC. Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer. Lung Cancer. 2013;81(3):354–61.

    Article  PubMed  Google Scholar 

  21. Selvakumaran M, Amaravadi RK, Vasilevskaya IA, O’Dwyer PJ. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin Cancer Res. 2013;19(11):2995–3007.

    Article  CAS  PubMed  Google Scholar 

  22. Guo XL, Li D, Sun K, Wang J, Liu Y, Song JR, Zhao QD, Zhang SS, Deng WJ, Zhao X, et al. Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J Mol Med. 2013;91(4):473–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, Aghi MK. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72(7):1773–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Bareford MD, Hamed HA, Tang Y, Cruickshanks N, Burow ME, Fisher PB, Moran RG, Nephew KP, Grant S, Dent P. Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Autophagy. 2011;7(10):1261–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature. 1997;390(6658):404–7.

    Article  CAS  PubMed  Google Scholar 

  26. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000.

    Article  CAS  PubMed  Google Scholar 

  28. Schneider BP, Gray RJ, Radovich M, Shen F, Vance G, Li L, Jiang G, Miller KD, Gralow JR, Dickler MN, et al. Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial. Clin Cancer Res. 2013;19(5):1281–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Koutras AK, Antonacopoulou AG, Eleftheraki AG, Dimitrakopoulos FI, Koumarianou A, Varthalitis I, Fostira F, Sgouros J, Briasoulis E, Bournakis E, et al. Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab. Pharmacogenomics J. 2012;12(6):468–75.

    Article  CAS  PubMed  Google Scholar 

  30. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8(4):299–309.

    Article  CAS  PubMed  Google Scholar 

  31. Fernando NT, Koch M, Rothrock C, Gollogly LK, D’Amore PA, Ryeom S, Yoon SS. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res. 2008;14(5):1529–39.

    Article  CAS  PubMed  Google Scholar 

  32. Xiong YQ, Sun HC, Zhang W, Zhu XD, Zhuang PY, Zhang JB, Wang L, Wu WZ, Qin LX, Tang ZY. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res. 2009;15(15):4838–46.

    Article  CAS  PubMed  Google Scholar 

  33. Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, et al. Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol. 2009;175(6):2657–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, Gatter KC, Pezzella F. Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med. 2013;2(4):427–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Kaessmeyer S, Bhoola K, Baltic S, Thompson P, Plendl J. Lung cancer neovascularisation: cellular and molecular interaction between endothelial and lung cancer cells. Immunobiology. 2014;219(4):308–14.

    Article  CAS  PubMed  Google Scholar 

  36. van der Schaft DW, Hillen F, Pauwels P, Kirschmann DA, Castermans K, Egbrink MG, Tran MG, Sciot R, Hauben E, Hogendoorn PC, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res. 2005;65(24):11520–8.

    Article  PubMed  CAS  Google Scholar 

  37. Vartanian AA, Stepanova EV, Gutorov SL, Solomko E, Grigorieva IN, Sokolova IN, Baryshnikov AY, Lichinitser MR. Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma. Can J Urol. 2009;16(4):4726–32.

    PubMed  Google Scholar 

  38. Gaiser T, Becker MR, Meyer J, Habel A, Siegelin MD. p53-mediated inhibition of angiogenesis in diffuse low-grade astrocytomas. Neurochem Int. 2009;54(7):458–63.

    Article  CAS  PubMed  Google Scholar 

  39. Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Rao Lelsani PC, Yadav S, Awasthi S. Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010;126(6):1327–38.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008;5(4):194–204.

    Article  CAS  PubMed  Google Scholar 

  41. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932–6.

    Article  CAS  PubMed  Google Scholar 

  42. Rapisarda A, Melillo G. Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resistance Updat. 2009;12(3):74–80.

    Article  CAS  Google Scholar 

  43. Dang DT, Chun SY, Burkitt K, Abe M, Chen S, Havre P, Mabjeesh NJ, Heath EI, Vogelzang NJ, Cruz-Correa M, et al. Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res. 2008;68(6):1872–80.

    Article  CAS  PubMed  Google Scholar 

  44. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463–75.

    Article  CAS  PubMed  Google Scholar 

  45. Jia Z, Zhang J, Wei D, Wang L, Yuan P, Le X, Li Q, Yao J, Xie K. Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A. Cancer Res. 2007;67(10):4878–85.

    Article  CAS  PubMed  Google Scholar 

  46. Yu Q, Chen L, You Y, Zou C, Zhang Y, Liu Q, Cheng F. Erythropoietin combined with granulocyte colony stimulating factor enhances MMP-2 expression in mesenchymal stem cells and promotes cell migration. Mol Medicine Rep. 2011;4(1):31–6.

    CAS  Google Scholar 

  47. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15(1):35–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol/Hematol. 2006;59(1):15–26.

    Article  Google Scholar 

  49. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–74.

    Article  CAS  PubMed  Google Scholar 

  50. Kerbel RS. Tumor angiogenesis. New Engl J Med. 2008;358(19):2039–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA. 2011;108(9):3749–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Martinez-Poveda B, Gomez V, Alcaide-German M, Perruca S, Vazquez S, Alba LE, Casanovas O, Garcia-Bermejo ML, Peso L, Jimenez B. Non-invasive monitoring of hypoxia-inducible factor activation by optical imaging during antiangiogenic treatment in a xenograft model of ovarian carcinoma. Int J Oncol. 2011;39(3):543–52.

    CAS  PubMed  Google Scholar 

  53. von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F. Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res. 2011;17(19):6192–205.

    Article  Google Scholar 

  54. Xu H, Rahimpour S, Nesvick CL, Zhang X, Ma J, Zhang M, Zhang G, Wang L, Yang C, Hong CS, et al. Activation of hypoxia signaling induces phenotypic transformation of glioma cells: implications for bevacizumab antiangiogenic therapy. Oncotarget. 2015;6(14):11882–93.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell. 2004;5(1):13–7.

    Article  CAS  PubMed  Google Scholar 

  56. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Shi D, Xie F, Zhang Y, Tian Y, Chen W, Fu L, Wang J, Guo W, Kang T, Huang W, et al. TFAP2A regulates nasopharyngeal carcinoma growth and survival by targeting HIF-1alpha signaling pathway. Cancer Prevent Res. 2014;7(2):266–77.

    Article  CAS  Google Scholar 

  58. Shi D, Guo W, Chen W, Fu L, Wang J, Tian Y, Xiao X, Kang T, Huang W, Deng W. Nicotine promotes proliferation of human nasopharyngeal carcinoma cells by regulating alpha7AChR, ERK, HIF-1alpha and VEGF/PEDF signaling. PLoS One. 2012;7(8):e43898.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Hammond EM, Asselin MC, Forster D, O’Connor JP, Senra JM, Williams KJ. The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin Oncol. 2014;26(5):277–88.

    Article  CAS  Google Scholar 

  60. Kuiper C, Dachs GU, Munn D, Currie MJ, Robinson BA, Pearson JF, Vissers MC. Increased Tumor Ascorbate is Associated with Extended Disease-Free Survival and Decreased Hypoxia-Inducible Factor-1 Activation in Human Colorectal Cancer. Front Oncol. 2014;4:10.

    PubMed Central  PubMed  Google Scholar 

  61. Adams JM, Difazio LT, Rolandelli RH, Lujan JJ, Hasko G, Csoka B, Selmeczy Z, Nemeth ZH. HIF-1: a key mediator in hypoxia. Acta Physiol Hung. 2009;96(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  62. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.

    Article  CAS  PubMed  Google Scholar 

  63. Patel SA, Simon MC. Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ. 2008;15(4):628–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Yang SL, Liu LP, Jiang JX, Xiong ZF, He QJ, Wu C. The correlation of expression levels of HIF-1alpha and HIF-2alpha in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients’ clinical outcome. Jpn J Clin Oncol. 2014;44(2):159–67.

    Article  PubMed  Google Scholar 

  66. Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, Dische S, Sivridis E, Harris AL. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol. 2006;24(5):727–35.

    Article  CAS  PubMed  Google Scholar 

  67. Wu F, Zhang J, Liu Y, Zheng Y, Hu N. HIF1 alpha genetic variants and protein expressions determine the response to platinum based chemotherapy and clinical outcome in patients with advanced NSCLC. Cell Phys Biochem. 2013;32(6):1566–76.

    CAS  Google Scholar 

  68. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. De Palma M, Venneri MA, Galli R, Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8(3):211–26.

    Article  PubMed  CAS  Google Scholar 

  70. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13(3):206–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Lee GW, Go SI, Cho YJ, Jeong YY, Kim HC, Lee J, Hwang YS, Ko GH, Lee JH, Kim DC, et al. Hypoxia-inducible factor-1alpha and excision repair cross-complementing 1 in patients with small cell lung cancer who received front-line platinum-based chemotherapy: a retrospective study. J Thorac Oncol. 2012;7(3):528–34.

    Article  CAS  PubMed  Google Scholar 

  72. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, et al. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 2004;64(19):6845–8.

    Article  CAS  PubMed  Google Scholar 

  73. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2004;3(3):233–44.

    CAS  PubMed  Google Scholar 

  74. Wan X, Shen N, Mendoza A, Khanna C, Helman LJ. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia. 2006;8(5):394–401.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther. 2008;7(11):3598–608.

    Article  CAS  PubMed  Google Scholar 

  76. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005;65(19):9047–55.

    Article  CAS  PubMed  Google Scholar 

  77. Hartwich J, Orr WS, Ng CY, Spence Y, Morton C, Davidoff AM. HIF-1alpha activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts. J Pediatr Surg. 2013;48(1):39–46.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Gehrs B, Raffeld M, Kinders RJ, Parchment R, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther. 2009;8(7):1867–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–9.

    Article  CAS  PubMed  Google Scholar 

  80. Gil MJ, de Las Penas R, Reynes G, Balana C, Perez-Segura P, Garcia-Velasco A, Mesia C, Gallego O, Fernandez-Chacon C, Martinez-Garcia M, et al. Bevacizumab plus irinotecan in recurrent malignant glioma shows high overall survival in a multicenter retrospective pooled series of the Spanish Neuro-Oncology Research Group (GEINO). Anticancer Drugs. 2012;23(6):659–65.

    Article  CAS  PubMed  Google Scholar 

  81. Pencreach E, Guerin E, Nicolet C, Lelong-Rebel I, Voegeli AC, Oudet P, Larsen AK, Gaub MP, Guenot D. Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1alpha axis. Clin Cancer Res. 2009;15(4):1297–307.

    Article  CAS  PubMed  Google Scholar 

  82. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Investig. 2010;120(1):127–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Rouschop KM, Ramaekers CH, Schaaf MB, Keulers TG, Savelkouls KG, Lambin P, Koritzinsky M, Wouters BG. Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother Oncol. 2009;92(3):411–6.

    Article  CAS  PubMed  Google Scholar 

  84. Papandreou I, Lim AL, Laderoute K, Denko NC. Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ. 2008;15(10):1572–81.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892–903.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, Gibson SB. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy. 2008;4(2):195–204.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29(10):2570–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Liu XW, Su Y, Zhu H, Cao J, Ding WJ, Zhao YC, He QJ, Yang B. HIF-1alpha-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. Pharmacol Res. 2010;62(5):416–25.

    Article  PubMed  CAS  Google Scholar 

  89. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3(3):187–97.

    Article  CAS  PubMed  Google Scholar 

  90. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007;26(7):1749–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Zhang N, Ji N, Jiang WM, Li ZY, Wang M, Wen JM, Li Y, Chen X, Chen JM. Hypoxia-induced autophagy promotes human prostate stromal cells survival and ER-stress. Biochem Biophys Res Commun. 2015;464(4):1107–12.

    Article  CAS  PubMed  Google Scholar 

  92. Wu HM, Jiang ZF, Ding PS, Shao LJ, Liu RY. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci Rep. 2015;5:12291.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5(9):726–34.

    Article  CAS  PubMed  Google Scholar 

  94. Petersen M, Hofius D, Andersen SU. Signaling unmasked: autophagy and catalase promote programmed cell death. Autophagy. 2014;10(3):520–1.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA. 2003;100(25):15077–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Tian Y, Kuo CF, Sir D, Wang L, Govindarajan S, Petrovic LM, Ou JH. Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ. 2015;22(6):1025–34.

    Article  CAS  PubMed  Google Scholar 

  97. Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu WG. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol. 2010;12(7):665–75.

    Article  CAS  PubMed  Google Scholar 

  98. Akin D, Wang SK, Habibzadegah-Tari P, Law B, Ostrov D, Li M, Yin XM, Kim JS, Horenstein N, Dunn WA Jr. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10(11):2021–35.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Laddha SV, Ganesan S, Chan CS, White E. Mutational landscape of the essential autophagy gene BECN1 in human cancers. Mol Cancer Res. 2014;12(4):485–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Ren JH, He WS, Nong L, Zhu QY, Hu K, Zhang RG, Huang LL, Zhu F, Wu G. Acquired cisplatin resistance in human lung adenocarcinoma cells is associated with enhanced autophagy. Cancer Biother Radiopharm. 2010;25(1):75–80.

    Article  CAS  PubMed  Google Scholar 

  101. Xiong HY, Guo XL, Bu XX, Zhang SS, Ma NN, Song JR, Hu F, Tao SF, Sun K, Li R, et al. Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell. Cancer Lett. 2010;288(1):68–74.

    Article  CAS  PubMed  Google Scholar 

  102. Oberle C, Huai J, Reinheckel T, Tacke M, Rassner M, Ekert PG, Buellesbach J, Borner C. Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes. Cell Death Differ. 2010;17(7):1167–78.

    Article  CAS  PubMed  Google Scholar 

  103. Onodera J, Ohsumi Y. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J Biol Chem. 2005;280(36):31582–6.

    Article  CAS  PubMed  Google Scholar 

  104. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6.

    Article  CAS  PubMed  Google Scholar 

  105. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. New Engl J Med. 2013;368(19):1845–6.

    Article  CAS  PubMed  Google Scholar 

  106. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7(12):961–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Morselli E, Galluzzi L, Kepp O, Vicencio JM, Criollo A, Maiuri MC, Kroemer G. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta. 2009;1793(9):1524–32.

    Article  CAS  PubMed  Google Scholar 

  108. Thorburn A, Thamm DH, Gustafson DL. Autophagy and cancer therapy. Mol Pharmacol. 2014;85(6):830–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  109. Chaachouay H, Ohneseit P, Toulany M, Kehlbach R, Multhoff G, Rodemann HP. Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother Oncol. 2011;99(3):287–92.

    Article  CAS  PubMed  Google Scholar 

  110. Xie BS, Zhao HC, Yao SK, Zhuo DX, Jin B, Lv DC, Wu CL, Ma DL, Gao C, Shu XM, et al. Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells. Int J Mol Med. 2011;27(4):599–606.

    CAS  PubMed  Google Scholar 

  111. Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, et al. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. 2011;29(2):142–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P, Macleod KF. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol. 2007;27(17):6229–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY, et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy. 2011;7(10):1159–72.

    Article  CAS  PubMed  Google Scholar 

  114. Motzer RJ, Michaelson MD, Rosenberg J, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Wilding G. Sunitinib efficacy against advanced renal cell carcinoma. J Urol. 2007;178(5):1883–7.

    Article  CAS  PubMed  Google Scholar 

  115. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13(5):1367–73.

    Article  CAS  PubMed  Google Scholar 

  117. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17(23):7337–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Abdel-Aziz AK, Shouman S, El-Demerdash E, Elgendy M, Abdel-Naim AB. Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries. Chem Biol Interact. 2014;217:28–40.

    Article  CAS  PubMed  Google Scholar 

  119. Ikeda T, Ishii KA, Saito Y, Miura M, Otagiri A, Kawakami Y, Shimano H, Hara H, Takekoshi K. Inhibition of autophagy enhances sunitinib-induced cytotoxicity in rat pheochromocytoma PC12 cells. J P Sci. 2013;121(1):67–73.

    CAS  Google Scholar 

  120. Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther. 2009;8(2):394–406.

    Article  CAS  PubMed  Google Scholar 

  121. Santoni M, Amantini C, Morelli MB, Liberati S, Farfariello V, Nabissi M, Bonfili L, Eleuteri AM, Mozzicafreddo M, Burattini L, et al. Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells. Br J Cancer. 2013;109(4):1040–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Zhao Y, Xue T, Yang X, Zhu H, Ding X, Lou L, Lu W, Yang B, He Q. Autophagy plays an important role in sunitinib-mediated cell death in H9c2 cardiac muscle cells. Toxicol Appl Pharmacol. 2010;248(1):20–7.

    Article  CAS  PubMed  Google Scholar 

  123. Lin CI, Whang EE, Lorch JH, Ruan DT. Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer. Surgery. 2012;152(6):1142–9.

    Article  PubMed  Google Scholar 

  124. Tai WT, Shiau CW, Chen HL, Liu CY, Lin CS, Cheng AL, Chen PJ, Chen KF. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells. Cell Death Dis. 2013;4:e485.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Liu, J., Fan, L., Wang, H. et al. Autophagy, a double-edged sword in anti-angiogenesis therapy. Med Oncol 33, 10 (2016). https://doi.org/10.1007/s12032-015-0721-9

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