Skip to main content
SpringerLink
Log in

Hypoxia-Induced Resistance to Chemotherapy in Cancer

  • Chapter
  • First Online:
Hypoxia and Cancer Metastasis

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1136))

Abstract

A major barrier to the successful management of cancer is the development of resistance to therapy. Chemotherapy resistance can either be an intrinsic property of malignant cells developed prior to therapy, or acquired following exposure to anti-cancer drugs. Given the impact of drug resistance to the overall poor survival of cancer patients, there is an urgent need to better understand the molecular pathways regulating this malignant phenotype. In this chapter we describe some of the molecular pathways that contribute to drug resistance in cancer, the role of a microenvironment deficient in oxygen (hypoxia) in malignant progression, and how hypoxia can be a significant factor in the development of drug resistance. We conclude by proposing potential therapeutic approaches that take advantage of a hypoxic microenvironment to chemosensitize therapy-resistant tumours.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Campos L et al (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096

    CAS  PubMed  Google Scholar 

  2. Sugawara I, Akiyama S, Scheper RJ, Itoyama S (1997) Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett 112:23–31. https://doi.org/10.1016/S0304-3835(96)04542-9

    Article  CAS  PubMed  Google Scholar 

  3. Britten RA, Green JA, Warenius HM (1992) Cellular glutathione (GSH) and glutathione S-transferase (GST) activity in human ovarian tumor biopsies following exposure to alkylating agents. Int J Radiat Oncol Biol Phys 24:527–531

    Article  CAS  PubMed  Google Scholar 

  4. Liang BC (1996) Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J Neuro-Oncol 29:149–155

    Article  CAS  Google Scholar 

  5. Bonetti A et al (1998) bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 4:2331–2336

    CAS  PubMed  Google Scholar 

  6. St Croix B, Man S, Kerbel RS (1998) Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors. Cancer Lett 131:35–44

    Article  CAS  PubMed  Google Scholar 

  7. Graham CH et al (1994) Rapid acquisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor alkylating agents. J Natl Cancer Inst 86:975–982

    Article  CAS  PubMed  Google Scholar 

  8. Kobayashi H et al (1993) Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci U S A 90:3294–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Croix BS et al (1996) Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells. J Natl Cancer Inst 88:1285–1296

    Article  CAS  PubMed  Google Scholar 

  10. Kurtova AV et al (2015) Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517:209–213. https://doi.org/10.1038/nature14034

    Article  CAS  PubMed  Google Scholar 

  11. Prieto-Vila M, Takahashi RU, Usuba W, Kohama I, Ochiya T (2017) Drug resistance driven by Cancer stem cells and their niche. Int J Mol Sci 18:ARTN 2574. https://doi.org/10.3390/ijms18122574

    Article  CAS  Google Scholar 

  12. Eyler CE, Rich JN (2008) Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 26:2839–2845. https://doi.org/10.1200/JCO.2007.15.1829

    Article  CAS  PubMed  Google Scholar 

  13. Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14:275–291. https://doi.org/10.1016/j.stem.2014.02.006

    Article  CAS  PubMed  Google Scholar 

  14. Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2:3. https://doi.org/10.1186/2001-1326-2-3

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sharif T et al (2017) Autophagic homeostasis is required for the pluripotency of cancer stem cells. Autophagy 13:264–284. https://doi.org/10.1080/15548627.2016.1260808

    Article  CAS  PubMed  Google Scholar 

  16. Pagotto A et al (2017) Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis 8:e2943. https://doi.org/10.1038/cddis.2017.327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596. https://doi.org/10.1242/jcs.116392

    Article  CAS  PubMed  Google Scholar 

  18. Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I (2018) The hypoxic tumour microenvironment. Oncogene 7:10. https://doi.org/10.1038/s41389-017-0011-9

    Article  CAS  Google Scholar 

  19. Weaver VM et al (2002) beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2:205–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schrader J et al (2011) Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53:1192–1205. https://doi.org/10.1002/hep.24108

    Article  CAS  PubMed  Google Scholar 

  21. Pickup MW, Mouw JK, Weaver VM (2014) The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 15:1243–1253. https://doi.org/10.15252/embr.201439246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254. https://doi.org/10.1016/j.ccr.2005.08.010

    Article  CAS  PubMed  Google Scholar 

  23. Hayashi M et al (2012) Evaluation of tumor stiffness by elastography is predictive for pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer. Ann Surg Oncol 19:3042–3049. https://doi.org/10.1245/s10434-012-2343-1

    Article  PubMed  Google Scholar 

  24. Rice AJ et al (2017) Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogene 6:e352. https://doi.org/10.1038/oncsis.2017.54

    Article  CAS  Google Scholar 

  25. Jiang H et al (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22:851–860. https://doi.org/10.1038/nm.4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Munson JM, Shieh AC (2014) Interstitial fluid flow in cancer: implications for disease progression and treatment. Cancer Manag Res 6:317–328. https://doi.org/10.2147/Cmar.S65444

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ogiso Y, Tomida A, Lei S, Omura S, Tsuruo T (2000) Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. Cancer Res 60:2429–2434

    CAS  PubMed  Google Scholar 

  28. Shen J et al (1987) Coinduction of glucose-regulated proteins and doxorubicin resistance in Chinese hamster cells. Proc Natl Acad Sci U S A 84:3278–3282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hughes CS, Shen JW, Subjeck JR (1989) Resistance to etoposide induced by three glucose-regulated stresses in Chinese hamster ovary cells. Cancer Res 49:4452–4454

    CAS  PubMed  Google Scholar 

  30. Vaupel PW (1997) The influence of tumor blood flow and microenvironmental factors on the efficacy of radiation, drugs and localized hyperthermia. Klin Padiatr 209:243–249. https://doi.org/10.1055/s-2008-1043957

    Article  CAS  PubMed  Google Scholar 

  31. Vaupel PW, Frinak S, Bicher HI (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41:2008–2013

    CAS  PubMed  Google Scholar 

  32. Olive KP et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461. https://doi.org/10.1126/science.1171362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD (2011) Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look. Cancer Discov 1:291–296. https://doi.org/10.1158/2159-8290.CD-11-0136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zitvogel L et al (2015) Cancer and the gut microbiota: an unexpected link. Sci Transl Med 7:271ps271. https://doi.org/10.1126/scitranslmed.3010473

    Article  CAS  Google Scholar 

  35. Panebianco C, Andriulli A, Pazienza V (2018) Pharmacomicrobiomics: exploiting the drug-microbiota interactions in anticancer therapies. Microbiome 6:92. https://doi.org/10.1186/s40168-018-0483-7

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF (2018) The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359:1366–1370. https://doi.org/10.1126/science.aar6918

    Article  CAS  PubMed  Google Scholar 

  37. Geller LT, Straussman R (2018) Intratumoral bacteria may elicit chemoresistance by metabolizing anticancer agents. Mol Cell Oncol 5:e1405139. https://doi.org/10.1080/23723556.2017.1405139

    Article  CAS  PubMed  Google Scholar 

  38. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659. https://doi.org/10.1056/NEJM198612253152606

    Article  CAS  PubMed  Google Scholar 

  39. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:S0092-8674(11)00127-9 [pii] https://doi.org/10.1016/j.cell.2011.02.013

  40. Binnewies M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24:541–550. https://doi.org/10.1038/s41591-018-0014-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Medler TR, Cotechini T, Coussens LM (2015) Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance. Trends Cancer 1:66–75. https://doi.org/10.1016/j.trecan.2015.07.008

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zheng Y et al (2009) Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114:3625–3628. https://doi.org/10.1182/blood-2009-05-220285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cotechini T, Medler TR, Coussens LM (2015) Myeloid cells as targets for therapy in solid tumors. Cancer J 21:343–350. https://doi.org/10.1097/PPO.0000000000000132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Affara NI et al (2014) B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25:809–821. https://doi.org/10.1016/j.ccr.2014.04.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. DeNardo DG et al (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102. https://doi.org/10.1016/j.ccr.2009.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shiao SL et al (2015) TH2-polarized CD4(+) T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res 3:518–525. https://doi.org/10.1158/2326-6066.CIR-14-0232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Parry RV et al (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553. doi:25/21/9543 [pii] https://doi.org/10.1128/MCB.25.21.9543-9553.2005

  48. Dong H et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. doi:nm730 [pii] https://doi.org/10.1038/nm730

  49. Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334. https://doi.org/10.1146/annurev.immunol.21.120601.141110

    Article  CAS  PubMed  Google Scholar 

  50. Chen J, Jiang CC, Jin L, Zhang XD (2015) Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 27:409–416. https://doi.org/10.1093/annonc/mdv615

    Article  PubMed  Google Scholar 

  51. Muenst S et al (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146:15–24. https://doi.org/10.1007/s10549-014-2988-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hamanishi J et al(2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 104:3360–3365. doi:0611533104 [pii] https://doi.org/10.1073/pnas.0611533104

  53. Inman BA et al (2007) PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109:1499–1505. https://doi.org/10.1002/cncr.22588

    Article  CAS  PubMed  Google Scholar 

  54. Konishi J et al(2004) B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 10:5094–5100. doi:10/15/5094 [pii] https://doi.org/10.1158/1078-0432.CCR-04-0428

  55. Shi SJ et al (2013) B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One 8:e76012. https://doi.org/10.1371/journal.pone.0076012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nduom EK et al (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro-Oncology 18:195–205. https://doi.org/10.1093/neuonc/nov172

    Article  CAS  PubMed  Google Scholar 

  57. Madore J et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28:245–253. https://doi.org/10.1111/pcmr.12340

    Article  CAS  PubMed  Google Scholar 

  58. Chen X et al (2008) Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biol Ther 7:622–627

    Article  CAS  PubMed  Google Scholar 

  59. Chen BJ et al (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 19:3462–3473. https://doi.org/10.1158/1078-0432.CCR-13-0855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Black M et al (2016) Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 7:10557–10567. https://doi.org/10.18632/oncotarget.7235

    Article  PubMed  PubMed Central  Google Scholar 

  61. Azuma T et al (2008) B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111:3635–3643 doi:blood-2007-11-123141 [pii] https://doi.org/10.1182/blood-2007-11-123141

  62. Harris AL (2002) Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  CAS  PubMed  Google Scholar 

  63. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634. https://doi.org/10.1038/onc.2009.441

    Article  CAS  PubMed  Google Scholar 

  64. Maxwell PH et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275

    Article  CAS  PubMed  Google Scholar 

  65. Jaakkola P et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472. https://doi.org/10.1126/science.1059796

    Article  CAS  PubMed  Google Scholar 

  66. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861. https://doi.org/10.1126/science.1068592

    Article  CAS  PubMed  Google Scholar 

  67. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686. https://doi.org/10.1101/gad.924501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Semenza GL (2002) Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med 41:79–83

    Article  CAS  PubMed  Google Scholar 

  69. Wood SM et al (1998) Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of hif-1alpha-dependent and -independent hypoxia-inducible gene expression. J Biol Chem 273:8360–8368

    Article  CAS  PubMed  Google Scholar 

  70. Forsythe JA et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Krock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2:1117–1133. https://doi.org/10.1177/1947601911423654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nagy JA, Chang SH, Dvorak AM, Dvorak HF (2009) Why are tumour blood vessels abnormal and why is it important to know? Br J Cancer 100:865–869. https://doi.org/10.1038/sj.bjc.6604929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zampell JC et al (2012) HIF-1alpha coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J 26:1027–1039. https://doi.org/10.1096/fj.11-195321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bordry N et al (2018) Lymphatic vessel density is associated with CD8(+) T cell infiltration and immunosuppressive factors in human melanoma. Oncoimmunology 7:e1462878. https://doi.org/10.1080/2162402X.2018.1462878

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ruan K, Song G, Ouyang G (2009) Role of hypoxia in the hallmarks of human cancer. J Cell Biochem 107:1053–1062. https://doi.org/10.1002/jcb.22214

    Article  CAS  PubMed  Google Scholar 

  76. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26:638–648. https://doi.org/10.1259/0007-1285-26-312-638

    Article  CAS  PubMed  Google Scholar 

  77. Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fletcher GH (1984) Radiation and drug resistance of breast cancer. Am J Clin Oncol 7:617–624

    Article  CAS  PubMed  Google Scholar 

  79. Overgaard J (2007) Hypoxic radiosensitization: adored and ignored. J Clin Oncol 25:4066–4074. https://doi.org/10.1200/JCO.2007.12.7878

    Article  PubMed  Google Scholar 

  80. Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192. https://doi.org/10.1038/nrc2344

    Article  CAS  PubMed  Google Scholar 

  81. Horsman MR, Overgaard J (2016) The impact of hypoxia and its modification of the outcome of radiotherapy. J Radiat Res 57(Suppl 1):i90–i98. https://doi.org/10.1093/jrr/rrw007

    Article  PubMed  PubMed Central  Google Scholar 

  82. Teicher BA (1994) Hypoxia and drug resistance. Cancer Metastasis Rev 13:139–168

    Article  CAS  PubMed  Google Scholar 

  83. Hockel M et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56:4509–4515

    CAS  PubMed  Google Scholar 

  84. Brizel DM et al (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56:941–943

    CAS  PubMed  Google Scholar 

  85. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW (1997) Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38:285–289

    Article  CAS  PubMed  Google Scholar 

  86. Lartigau E et al (1997) Intratumoral oxygen tension in metastatic melanoma. Melanoma Res 7:400–406

    Article  CAS  PubMed  Google Scholar 

  87. Movsas B et al (2000) Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2) study. Cancer 89:2018–2024

    Article  CAS  PubMed  Google Scholar 

  88. Movsas B et al (1999) Hypoxic regions exist in human prostate carcinoma. Urology 53:11–18

    Article  CAS  PubMed  Google Scholar 

  89. Milosevic M et al (2012) Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res 18:2108–2114. https://doi.org/10.1158/1078-0432.CCR-11-2711

    Article  CAS  PubMed  Google Scholar 

  90. Cairns RA, Kalliomaki T, Hill RP (2001) Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 61:8903–8908

    CAS  PubMed  Google Scholar 

  91. Cairns RA, Hill RP (2004) Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 64:2054–2061

    Article  CAS  PubMed  Google Scholar 

  92. Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci U S A 85:9533–9537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang L, Hill RP (2004) Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res 64:4180–4189

    Article  CAS  PubMed  Google Scholar 

  94. Cuvier C, Jang A, Hill RP (1997) Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion. Clin Exp Metastasis 15:19–25

    Article  CAS  PubMed  Google Scholar 

  95. Graham CH, Forsdike J, Fitzgerald CF, Macdonald-Goodfellow S (1999) Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int J Cancer 80:617–623

    Article  CAS  PubMed  Google Scholar 

  96. Postovit LM, Adams MA, Lash GE, Heaton JP, Graham CH (2002) Oxygen-mediated regulation of tumour cell invasiveness: involvement of a nitric oxide signalling pathway. J Biol Chem 277:35730–35737

    Article  CAS  PubMed  Google Scholar 

  97. Postovit LM, Adams MA, Lash GE, Heaton JP, Graham CH (2004) Nitric oxide-mediated regulation of hypoxia-induced B16F10 melanoma metastasis. Int J Cancer 108:47–53. https://doi.org/10.1002/ijc.11556

    Article  CAS  PubMed  Google Scholar 

  98. Graham CH, Fitzpatrick TE, McCrae KR (1998) Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood 91:3300–3307

    CAS  PubMed  Google Scholar 

  99. Graham CH, Postovit LM, Lash GE, Adams MA (2001) Ultra low levels of nitric oxide abrogate hypoxia-induced metastatic phenotypes: evidence that reduced nitric oxide mediates a key pathway in oxygen-regulated gene expression. Proc Am Assoc Cancer Res 42:794

    Google Scholar 

  100. Fitzpatrick TE, Graham CH (1998) Stimulation of plasminogen activator inhibitor-1 expression in immortalized human trophoblast cells cultured under low levels of oxygen. Exp Cell Res 245:155–162

    Article  CAS  PubMed  Google Scholar 

  101. Canning MT, Postovit LM, Clarke SH, Graham CH (2001) Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Exp Cell Res 267:88–94

    Article  CAS  PubMed  Google Scholar 

  102. Rofstad EK et al (2002) Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Res 62:1847–1853

    CAS  PubMed  Google Scholar 

  103. Liu Q et al (2017) Factors involved in cancer metastasis: a better understanding to "seed and soil" hypothesis. Mol Cancer 16:176. https://doi.org/10.1186/s12943-017-0742-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98–101

    CAS  PubMed  Google Scholar 

  105. Rankin EB, Nam JM, Giaccia AJ (2016) Hypoxia: signaling the metastatic Cascade. Trends Cancer 2:295–304. https://doi.org/10.1016/j.trecan.2016.05.006

    Article  PubMed  PubMed Central  Google Scholar 

  106. Sceneay J et al (2012) Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 72:3906–3911. https://doi.org/10.1158/0008-5472.CAN-11-3873

    Article  CAS  PubMed  Google Scholar 

  107. Sceneay J, Parker BS, Smyth MJ, Moller A (2013) Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2:e22355. https://doi.org/10.4161/onci.22355

    Article  PubMed  PubMed Central  Google Scholar 

  108. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221:3–12. https://doi.org/10.1002/path.2697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mazure NM, Pouyssegur J (2010) Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 22:177–180. https://doi.org/10.1016/j.ceb.2009.11.015

    Article  CAS  PubMed  Google Scholar 

  110. Rouschop KM et al (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127–141. https://doi.org/10.1172/JCI40027

    Article  CAS  PubMed  Google Scholar 

  111. Rzymski T et al (2010) Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29:4424–4435. https://doi.org/10.1038/onc.2010.191

    Article  CAS  PubMed  Google Scholar 

  112. Chhipa RR, Wu Y, Ip C (2011) AMPK-mediated autophagy is a survival mechanism in androgen-dependent prostate cancer cells subjected to androgen deprivation and hypoxia. Cell Signal 23:1466–1472. https://doi.org/10.1016/j.cellsig.2011.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Papandreou I, Lim AL, Laderoute K, Denko NC (2008) Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L. Cell Death Differ 15:1572–1581. https://doi.org/10.1038/cdd.2008.84

    Article  CAS  PubMed  Google Scholar 

  114. Ma Y et al (2014) Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. Oncotarget 5:9169–9182. https://doi.org/10.18632/oncotarget.2396

    Article  PubMed  PubMed Central  Google Scholar 

  115. Bellot G et al (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581. https://doi.org/10.1128/MCB.00166-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang H et al (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mazure NM, Pouyssegur J (2009) Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 5:868–869

    Article  PubMed  Google Scholar 

  118. Tracy K et al (2007) BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 27:6229–6242. https://doi.org/10.1128/MCB.02246-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sun Y et al (2015) Hypoxia-induced autophagy reduces radiosensitivity by the HIF-1alpha/miR-210/Bcl-2 pathway in colon cancer cells. Int J Oncol 46:750–756. https://doi.org/10.3892/ijo.2014.2745

    Article  CAS  PubMed  Google Scholar 

  120. Wang P et al (2017) Hypoxia inducible factor-1alpha regulates autophagy via the p27-E2F1 signaling pathway. Mol Med Rep 16:2107–2112. https://doi.org/10.3892/mmr.2017.6794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Azad MB et al (2008) Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 4:195–204

    Article  CAS  PubMed  Google Scholar 

  122. Kalra R, Jones AM, Kirk J, Adams GE, Stratford IJ (1993) The effect of hypoxia on acquired drug resistance and response to epidermal growth factor in Chinese hamster lung fibroblasts and human breast-cancer cells in vitro. Int J Cancer 54:650–655

    Article  CAS  PubMed  Google Scholar 

  123. Rice GC, Ling V, Schimke RT (1987) Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance. Proc Natl Acad Sci U S A 84:9261–9264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Smith E, Stratford IJ, Adams GE (1980) Cytotoxicity of adriamycin on aerobic and hypoxic chinese hamster V79 cells in vitro. Br J Cancer 42:568–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wilson RE, Keng PC, Sutherland RM (1989) Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia. J Natl Cancer Inst 81:1235–1240

    Article  CAS  PubMed  Google Scholar 

  126. Luk CK, Veinot-Drebot L, Tjan E, Tannock IF (1990) Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines. J Natl Cancer Inst 82:684–692

    Article  CAS  PubMed  Google Scholar 

  127. Sanna K, Rofstad EK (1994) Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int J Cancer 58:258–262

    Article  CAS  PubMed  Google Scholar 

  128. Comerford KM et al (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394

    CAS  PubMed  Google Scholar 

  129. Krishnamurthy P et al (2004) The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 279:24218–24225. https://doi.org/10.1074/jbc.M313599200

    Article  CAS  PubMed  Google Scholar 

  130. Sullivan R, Graham CH (2008) Chemosensitization of cancer by nitric oxide. Curr Pharm Des 14:1113–1123

    Article  CAS  PubMed  Google Scholar 

  131. Ricci MS, Zong WX (2006) Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11:342–357. https://doi.org/10.1634/theoncologist.11-4-342

    Article  CAS  PubMed  Google Scholar 

  132. Chang BD et al (1999) A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res 59:3761–3767

    CAS  PubMed  Google Scholar 

  133. Chang BD et al (2002) Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci U S A 99:389–394. https://doi.org/10.1073/pnas.012602599

    Article  CAS  PubMed  Google Scholar 

  134. Chang BD et al (1999) Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 18:4808–4818. https://doi.org/10.1038/sj.onc.1203078

    Article  CAS  PubMed  Google Scholar 

  135. Schwarze SR, Fu VX, Desotelle JA, Kenowski ML, Jarrard DF (2005) The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. Neoplasia 7:816–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62:1876–1883

    Google Scholar 

  137. Elmore LW et al (2002) Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction. J Biol Chem 277:35509–35515. https://doi.org/10.1074/jbc.M205477200

    Article  CAS  PubMed  Google Scholar 

  138. Roninson IB, Broude EV, Chang BD (2001) If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat 4:303–313. https://doi.org/10.1054/drup.2001.0213

    Article  CAS  PubMed  Google Scholar 

  139. Sullivan R, Paré GC, Frederiksen, L. J., Semenza, G. L. & Graham, C. H. (2008) Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 7, 1961–1973. doi:7/7/1961 [pii] https://doi.org/10.1158/1535-7163.MCT-08-0198

  140. Seimiya H et al (1999) Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells. Biochem Biophys Res Commun 260:365–370. https://doi.org/10.1006/bbrc.1999.0910

    Article  CAS  PubMed  Google Scholar 

  141. Yatabe N et al (2004) HIF-1-mediated activation of telomerase in cervical cancer cells. Oncogene 23:3708–3715. https://doi.org/10.1038/sj.onc.1207460

    Article  CAS  PubMed  Google Scholar 

  142. Nishi H et al (2004) Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT). Mol Cell Biol 24:6076–6083. https://doi.org/10.1128/MCB.24.13.6076-6083.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Anderson CJ, Hoare SF, Ashcroft M, Bilsland AE, Keith WN (2006) Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms. Oncogene 25:61–69. https://doi.org/10.1038/sj.onc.1209011

    Article  CAS  PubMed  Google Scholar 

  144. Sullivan R, Graham CH (2009) Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1. Mol Cancer Ther 8:1702-1713. doi:1535-7163.MCT-08-1090 [pii] https://doi.org/10.1158/1535-7163.MCT-08-1090

  145. Lee JG et al (2015) Autophagy contributes to the chemo-resistance of non-small cell lung cancer in hypoxic conditions. Respir Res 16:138. https://doi.org/10.1186/s12931-015-0285-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Harhaji-Trajkovic L, Vilimanovich U, Kravic-Stevovic T, Bumbasirevic V, Trajkovic V (2009) AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. J Cell Mol Med 13:3644–3654. https://doi.org/10.1111/j.1582-4934.2009.00663.x

    Article  CAS  PubMed  Google Scholar 

  147. Wu HM, Jiang ZF, Ding PS, Shao LJ, Liu RY (2015) Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci Rep 5:12291. https://doi.org/10.1038/srep12291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Song J et al (2009) Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy 5:1131–1144

    Article  CAS  PubMed  Google Scholar 

  149. Yang X et al (2018) Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1alpha activation. Int J Oncol 53:215–224. https://doi.org/10.3892/ijo.2018.4376

    Article  CAS  PubMed  Google Scholar 

  150. Liu XW et al (2010) HIF-1alpha-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. Pharmacol Res 62:416–425. https://doi.org/10.1016/j.phrs.2010.07.002

    Article  CAS  PubMed  Google Scholar 

  151. Peng X et al (2014) Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-alpha-mediated signaling. Cell Death Dis 5:e1367. https://doi.org/10.1038/cddis.2014.297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Notte A et al (2015) Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis. Int J Biochem Cell Biol 62:1–14. https://doi.org/10.1016/j.biocel.2015.02.010

    Article  CAS  PubMed  Google Scholar 

  153. Hu YL et al (2012) Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 72:1773–1783. https://doi.org/10.1158/0008-5472.CAN-11-3831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. He WS, Dai XF, Jin M, Liu CW, Rent JH (2012) Hypoxia-induced autophagy confers resistance of breast cancer cells to ionizing radiation. Oncol Res 20:251–258

    Article  PubMed  Google Scholar 

  155. Li Z et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513. https://doi.org/10.1016/j.ccr.2009.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Henze AT, Mazzone M (2016) The impact of hypoxia on tumor-associated macrophages. J Clin Invest 126:3672–3679. https://doi.org/10.1172/JCI84427

    Article  PubMed  PubMed Central  Google Scholar 

  157. Gebremeskel S, Johnston B (2015) Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget 6:41600–41619. https://doi.org/10.18632/oncotarget.6113

    Article  PubMed  PubMed Central  Google Scholar 

  158. Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74:665–674. https://doi.org/10.1158/0008-5472.CAN-13-0992

    Article  CAS  PubMed  Google Scholar 

  159. Noman MZ et al (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211:781–790. https://doi.org/10.1084/jem.20131916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bell EN et al (2007) Atrial natriuretic peptide attenuates hypoxia induced chemoresistance in prostate cancer cells. J Urol 177:751–756. doi:S0022-5347(06)02466-9 [pii] https://doi.org/10.1016/j.juro.2006.09.075

  161. Frederiksen LJ et al (2003) Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate. J Urol 170:1003–1007

    Article  CAS  PubMed  Google Scholar 

  162. Matthews NE, Adams MA, Maxwell LR, Gofton TE, Graham CH (2001) Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J Natl Cancer Inst 93:1879–1885

    Article  CAS  PubMed  Google Scholar 

  163. Muir CP, Adams MA, Graham CH (2006) Nitric oxide attenuates resistance to doxorubicin in three-dimensional aggregates of human breast carcinoma cells. Breast Cancer Res Treat 96:169–176

    Article  CAS  PubMed  Google Scholar 

  164. Postovit LM, Sullivan R, Adams MA, Graham CH (2005) Nitric oxide signalling and cellular adaptations to changes in oxygenation. Toxicology 208:235–248

    Article  CAS  PubMed  Google Scholar 

  165. Siemens DR et al (2008) Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 68:4746–4753. doi:68/12/4746 [pii] https://doi.org/10.1158/0008-5472.CAN-08-0054

  166. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Griffith OW, Stuehr DJ (1995) Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol 57:707–736

    Article  CAS  PubMed  Google Scholar 

  168. Hanafy KA, Krumenacker JS, Murad F (2001) NO, nitrotyrosine, and cyclic GMP in signal transduction. Med Sci Monit 7:801–819

    CAS  PubMed  Google Scholar 

  169. Stuehr DJ (1999) Mammalian nitric oxide synthases. Biochim Biophys Acta 1411:217–230

    Article  CAS  PubMed  Google Scholar 

  170. Whorton AR, Simonds DB, Piantadosi CA (1997) Regulation of nitric oxide synthesis by oxygen in vascular endothelial cells. Am J Physiol 272:L1161–L1166

    CAS  PubMed  Google Scholar 

  171. McCormick CC, Li WP, Calero M (2000) Oxygen tension limits nitric oxide synthesis by activated macrophages. Biochem J 350:709–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Frederiksen LJ et al (2007) Chemosensitization of cancer in vitro and in vivo by nitric oxide signaling. Clin Cancer Res 13:2199–2206. https://doi.org/10.1158/1078-0432.CCR-06-1807

    Article  CAS  PubMed  Google Scholar 

  173. Brune B, Zhou J (2007) Nitric oxide and superoxide: interference with hypoxic signaling. Cardiovasc Res 75:275–282. https://doi.org/10.1016/j.cardiores.2007.03.005

    Article  CAS  PubMed  Google Scholar 

  174. Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Science 302:1975–1978

    Article  CAS  PubMed  Google Scholar 

  175. Barsoum IB et al (2011) Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide. Cancer Res 71:7433–7441. https://doi.org/10.1158/0008-5472.CAN-11-2104

    Article  CAS  PubMed  Google Scholar 

  176. Mateo J, Garcia-Lecea M, Cadenas S, Hernandez C, Moncada S (2003) Regulation of hypoxia-inducible factor-1alpha by nitric oxide through mitochondria-dependent and -independent pathways. Biochem J 376:537–544. https://doi.org/10.1042/BJ20031155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Siemens DR, Heaton JP, Adams MA, Kawakami J, Graham CH (2009) Phase II study of nitric oxide donor for men with increasing prostate-specific antigen level after surgery or radiotherapy for prostate cancer. Urology 74:878–883. https://doi.org/10.1016/j.urology.2009.03.004

    Article  PubMed  Google Scholar 

  178. Yasuda H et al (2006) Randomized phase II trial comparing nitroglycerin plus vinorelbine and cisplatin with vinorelbine and cisplatin alone in previously untreated stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 24:688–694. https://doi.org/10.1200/JCO.2005.04.0436

    Article  CAS  PubMed  Google Scholar 

  179. Yasuda H et al (2006) Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma. Clin Cancer Res 12:6748–6757. https://doi.org/10.1158/1078-0432.CCR-06-1124

    Article  CAS  PubMed  Google Scholar 

  180. Swaika A, Hammond WA, Joseph RW (2015) Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol 67:4–17. https://doi.org/10.1016/j.molimm.2015.02.009

    Article  CAS  PubMed  Google Scholar 

  181. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6:8. https://doi.org/10.1186/s40425-018-0316-z

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Lori M. Minassian, Tiziana Cotechini, Erin Huitema & Charles H. Graham

Authors
  1. Lori M. Minassian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiziana Cotechini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erin Huitema
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles H. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles H. Graham .

Editor information

Editors and Affiliations

  1. Breast and Ovarian Cancer Program, Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniele M. Gilkes

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Minassian, L.M., Cotechini, T., Huitema, E., Graham, C.H. (2019). Hypoxia-Induced Resistance to Chemotherapy in Cancer. In: Gilkes, D. (eds) Hypoxia and Cancer Metastasis. Advances in Experimental Medicine and Biology, vol 1136. Springer, Cham. https://doi.org/10.1007/978-3-030-12734-3_9

Download citation

Publish with us

Policies and ethics

Search

Navigation