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Erschienen in: Medical Oncology 1/2016

01.01.2016 | Review Paper

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

verfasst von: Jiatao Liu, Lulu Fan, Hua Wang, Guoping Sun

Erschienen in: Medical Oncology | Ausgabe 1/2016

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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.
Literatur
1.
Zurück zum Zitat Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med. 1971;285(21):1182–6.PubMedCrossRef Folkman J. Tumor angiogenesis: therapeutic implications. New Engl J Med. 1971;285(21):1182–6.PubMedCrossRef
2.
Zurück zum Zitat 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.PubMed 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.PubMed
3.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
4.
Zurück zum Zitat Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res. 2007;74(2–3):72–84.PubMedCentralPubMedCrossRef Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res. 2007;74(2–3):72–84.PubMedCentralPubMedCrossRef
5.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
6.
Zurück zum Zitat 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.CrossRef 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.CrossRef
7.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
8.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
9.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
10.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
11.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
12.
Zurück zum Zitat Yorimitsu T, Klionsky DJ. Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol. 2007;17(6):279–85.PubMedCrossRef Yorimitsu T, Klionsky DJ. Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol. 2007;17(6):279–85.PubMedCrossRef
14.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
15.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
16.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
17.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
19.
Zurück zum Zitat 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.PubMed 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.PubMed
20.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
21.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
22.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
23.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
24.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
25.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000.PubMedCrossRef Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000.PubMedCrossRef
28.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
29.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
30.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
31.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
32.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
33.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
34.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
35.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
36.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
37.
Zurück zum Zitat 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 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
38.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
39.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
40.
Zurück zum Zitat Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008;5(4):194–204.PubMedCrossRef Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008;5(4):194–204.PubMedCrossRef
41.
42.
Zurück zum Zitat 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.CrossRef 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.CrossRef
43.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
44.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
45.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
46.
Zurück zum Zitat 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. 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.
47.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
48.
Zurück zum Zitat Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol/Hematol. 2006;59(1):15–26.CrossRef Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol/Hematol. 2006;59(1):15–26.CrossRef
49.
51.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
52.
Zurück zum Zitat 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.PubMed 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.PubMed
53.
Zurück zum Zitat 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.CrossRef 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.CrossRef
54.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
55.
Zurück zum Zitat Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell. 2004;5(1):13–7.PubMedCrossRef Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell. 2004;5(1):13–7.PubMedCrossRef
56.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
57.
Zurück zum Zitat 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.CrossRef 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.CrossRef
58.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
59.
Zurück zum Zitat 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.CrossRef 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.CrossRef
60.
Zurück zum Zitat 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.PubMedCentralPubMed 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.PubMedCentralPubMed
61.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
62.
Zurück zum Zitat Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.PubMedCrossRef Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393–410.PubMedCrossRef
64.
Zurück zum Zitat Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.PubMedCentralPubMedCrossRef Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.PubMedCentralPubMedCrossRef
65.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
66.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
67.
Zurück zum Zitat 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. 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.
68.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
69.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
70.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
71.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
72.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
73.
Zurück zum Zitat 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.PubMed 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.PubMed
74.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
75.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
76.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
77.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
78.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
79.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
80.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
81.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
82.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
83.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
84.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
85.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
86.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
87.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
88.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
89.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
90.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
91.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
92.
93.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
94.
95.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
96.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
97.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
98.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
99.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
100.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
101.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
102.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
103.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
104.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
105.
Zurück zum Zitat Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. New Engl J Med. 2013;368(19):1845–6.PubMedCrossRef Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. New Engl J Med. 2013;368(19):1845–6.PubMedCrossRef
107.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
109.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
110.
Zurück zum Zitat 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.PubMed 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.PubMed
111.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
112.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
113.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
114.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
115.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
116.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
117.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
118.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
119.
Zurück zum Zitat 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. 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.
120.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
121.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
122.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
123.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
124.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
Metadaten
Titel
Autophagy, a double-edged sword in anti-angiogenesis therapy
verfasst von
Jiatao Liu
Lulu Fan
Hua Wang
Guoping Sun
Publikationsdatum
01.01.2016
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 1/2016
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-015-0721-9

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