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Multiple Dynamics in Tumor Microenvironment Under Radiotherapy

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Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1263))

Abstract

The tumor microenvironment (TME) is an evolutionally low-level and embryonically featured tissue comprising heterogenic populations of malignant and stromal cells as well as noncellular components. Under radiotherapy (RT), the major modality for the treatment of malignant diseases [1], TME shows an adaptive response in multiple aspects that affect the efficacy of RT. With the potential clinical benefits, interests in RT combined with immunotherapy (IT) are intensified with a large scale of clinical trials underway for an array of cancer types. A better understanding of the multiple molecular aspects, especially the cross talks of RT-mediated energy reprogramming and immunoregulation in the irradiated TME (ITME), will be necessary for further enhancing the benefit of RT-IT modality. Coming studies should further reveal more mechanistic insights of radiation-induced instant or permanent consequence in tumor and stromal cells. Results from these studies will help to identify critical molecular pathways including cancer stem cell repopulation, metabolic rewiring, and specific communication between radioresistant cancer cells and the infiltrated immune active lymphocytes. In this chapter, we will focus on the following aspects: radiation-repopulated cancer stem cells (CSCs), hypoxia and re-oxygenation, reprogramming metabolism, and radiation-induced immune regulation, in which we summarize the current literature to illustrate an integrated image of the ITME. We hope that the contents in this chapter will be informative for physicians and translational researchers in cancer radiotherapy or immunotherapy.

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References

  1. Kesarwani P, Kant S, Prabhu A, Chinnaiyan P (2017) The interplay between metabolic remodeling and immune regulation in glioblastoma. Neuro-Oncology 19:1308–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schaue D, McBride WH (2015) Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 12:527–540

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ishii G (2017) Crosstalk between cancer associated fibroblasts and cancer cells in the tumor microenvironment after radiotherapy. EBioMedicine 17:7–8

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

    CAS  PubMed  Google Scholar 

  5. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Portella L, Scala S (2019) Ionizing radiation effects on the tumor microenvironment. Semin Oncol 46:254–260

    Article  CAS  PubMed  Google Scholar 

  7. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    Article  CAS  PubMed  Google Scholar 

  8. Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, Fazioli F, Pirozzi G, Papaccio G (2011) Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. FASEB J 25:2022–2030

    Article  CAS  PubMed  Google Scholar 

  9. Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273

    Article  CAS  PubMed  Google Scholar 

  10. Waterworth A (2004) Introducing the concept of breast cancer stem cells. Breast Cancer Res 6:53–54

    Article  CAS  PubMed  Google Scholar 

  11. Clarke MF (2005) A self-renewal assay for cancer stem cells. Cancer Chemother Pharmacol 56(Suppl 1):64–68

    Article  PubMed  Google Scholar 

  12. Dontu G, Liu S, Wicha MS (2005) Stem cells in mammary development and carcinogenesis: implications for prevention and treatment. Stem Cell Rev 1:207–213

    Article  CAS  PubMed  Google Scholar 

  13. Huntly BJ, Gilliland DG (2005) Cancer biology: summing up cancer stem cells. Nature 435:1169–1170

    Article  CAS  PubMed  Google Scholar 

  14. Ailles LE, Weissman IL (2007) Cancer stem cells in solid tumors. Curr Opin Biotechnol 18:460–466

    Article  CAS  PubMed  Google Scholar 

  15. Pajonk F, Vlashi E, McBride WH (2010) Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells 28:639–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stockler M, Wilcken NR, Ghersi D, Simes RJ (2000) Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat Rev 26:151–168

    Article  CAS  PubMed  Google Scholar 

  17. Baumann M, Krause M, Hill R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554

    Article  CAS  PubMed  Google Scholar 

  18. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells – perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344

    Article  CAS  PubMed  Google Scholar 

  19. Skvortsova I, Debbage P, Kumar V, Skvortsov S (2015) Radiation resistance: Cancer Stem Cells (CSCs) and their enigmatic pro-survival signaling. Semin Cancer Biol 35:39–44

    Article  CAS  PubMed  Google Scholar 

  20. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  CAS  PubMed  Google Scholar 

  21. Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785

    Article  PubMed  Google Scholar 

  22. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 3:e2428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Kurth I, Hein L, Mabert K, Peitzsch C, Koi L, Cojoc M, Kunz-Schughart L, Baumann M, Dubrovska A (2015) Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget 6:34494–34509

    Article  PubMed  PubMed Central  Google Scholar 

  24. Vlashi E, Pajonk F (2015) Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol 31:28–35

    Article  CAS  PubMed  Google Scholar 

  25. Kaufhold S, Garban H, Bonavida B (2016) Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res 35:84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Croker AK, Allan AL (2011) Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDH(hi)CD44 (+) human breast cancer cells. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-10011-11692-y

  27. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vlashi E, Chen AM, Boyrie S, Yu G, Nguyen A, Brower PA, Hess CB, Pajonk F (2016) Radiation-induced dedifferentiation of head and neck cancer cells into cancer stem cells depends on human papillomavirus status. Int J Radiat Oncol Biol Phys 94:1198–1206

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, Hung SC, Chang YL, Tsai ML, Lee YY, Ku HH, Chiou SH (2008) Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One 3:e2637

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wolff S (1989) Are radiation-induced effects hormetic? Science 245:575

    Article  CAS  PubMed  Google Scholar 

  31. Weichselbaum RR, Hallahan D, Fuks Z, Kufe D (1994) Radiation induction of immediate early genes: effectors of the radiation-stress response. Int J Radiat Oncol Biol Phys 30:229–234

    Article  CAS  PubMed  Google Scholar 

  32. Maity A, Kao GD, Muschel RJ, McKenna WG (1997) Potential molecular targets for manipulating the radiation response. Int J Radiat Oncol Biol Phys 37:639–653

    Article  CAS  PubMed  Google Scholar 

  33. Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B, Williams J (1997) Cell-cycle arrest versus cell death in cancer therapy. Nat Med 3:1034–1036

    Article  CAS  PubMed  Google Scholar 

  34. Schmidt-Ullrich RK, Dent P, Grant S, Mikkelsen RB, Valerie K (2000) Signal transduction and cellular radiation responses. Radiat Res 153:245–257

    Article  CAS  PubMed  Google Scholar 

  35. Valencia-Gonzalez HA, Ruiz G, Ortiz-Sanchez E, Garcia-Carranca A (2019) Cancer stem cells from tumor cell lines activate the DNA damage response pathway after ionizing radiation more efficiently than noncancer stem cells. Stem Cells Int 2019:7038953

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L, Mansukhani M, Murty VV, Gaciong Z, Meek SE, Piwnica-Worms H, Hibshoosh H, Parsons R (2005) Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7:193–204

    Article  CAS  PubMed  Google Scholar 

  37. Skvortsova (2008) Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics 8:4521–4533

    Article  CAS  PubMed  Google Scholar 

  38. Johannessen TC, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells – potential partners in glioma drug resistance? Cancer Treat Rev 34:558–567

    Article  CAS  PubMed  Google Scholar 

  39. Rich JN (2007) Cancer stem cells in radiation resistance. Cancer Res 67:8980–8984

    Article  CAS  PubMed  Google Scholar 

  40. Stecca C, Gerber GB (1998) Adaptive response to DNA-damaging agents: a review of potential mechanisms. Biochem Pharmacol 55:941–951

    Article  CAS  PubMed  Google Scholar 

  41. Wolff S (1998) The adaptive response in radiobiology: evolving insights and implications. Environ Health Perspect 106(Suppl 1):277–283

    Article  PubMed  PubMed Central  Google Scholar 

  42. Feinendegen LE (1999) The role of adaptive responses following exposure to ionizing radiation. Hum Exp Toxicol 18:426–432

    Article  CAS  PubMed  Google Scholar 

  43. Irie S, Li Y, Kanki H, Ohyama T, Deaven LL, Somlo S, Sato TA (2001) Identification of two Fas-associated phosphatase-1 (FAP-1) promoters in human cancer cells. DNA Seq 11:519–526

    Article  CAS  PubMed  Google Scholar 

  44. Feinendegen LE (2002) Reactive oxygen species in cell responses to toxic agents. Hum Exp Toxicol 21:85–90

    Article  CAS  PubMed  Google Scholar 

  45. Guo G, Yan-Sanders Y, Lyn-Cook BD, Wang T, Tamae D, Ogi J, Khaletskiy A, Li Z, Weydert C, Longmate JA, Huang T-T, Spitz DR, Oberley LW, Li JJ (2003) Manganese superoxide dismutase-mediated gene expression in radiation-induced adaptive responses. Mol Cell Biol 23:2362–2378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen Y, Gao Y, Zhang K, Li C, Pan Y, Chen J, Wang R, Chen L (2015) MicroRNAs as regulators of cisplatin resistance in lung cancer. Cell Physiol Biochem 37:1869–1880

    Article  CAS  PubMed  Google Scholar 

  47. Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, Ravani SA, Zavadil J, Borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, Barcellos-Hoff MH (2011) Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19:640–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chan T-S, Hsu C-C, Pai VC, Liao W-Y, Huang S-S, Tan K-T, Yen C-J, Hsu S-C, Chen W-Y, Shan Y-S (2016) Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med 213:2967–2988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hardee ME, Marciscano AE, Medina-Ramirez CM, Zagzag D, Narayana A, Lonning SM, Barcellos-Hoff MH (2012) Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-beta. Cancer Res 72:4119–4129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sultan M, Coyle KM, Vidovic D, Thomas ML, Gujar S, Marcato P (2016) Hide-and-seek: the interplay between cancer stem cells and the immune system. Carcinogenesis 38:107–118

    Article  CAS  Google Scholar 

  51. Cuiffo BG, Campagne A, Bell GW, Lembo A, Orso F, Lien EC, Bhasin MK, Raimo M, Hanson SE, Marusyk A (2014) MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis. Cell Stem Cell 15:762–774

    Article  CAS  PubMed  Google Scholar 

  52. Whiteside T (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen W-J, Ho C-C, Chang Y-L, Chen H-Y, Lin C-A, Ling T-Y, Yu S-L, Yuan S-S, Chen Y-JL, Lin C-Y (2014) Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun 5:3472

    Article  PubMed  CAS  Google Scholar 

  54. Lau EYT, Lo J, Cheng BYL, Ma MKF, Lee JMF, Ng JKY, Chai S, Lin CH, Tsang SY, Ma S (2016) Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-met/FRA1/HEY1 signaling. Cell Rep 15:1175–1189

    Article  CAS  PubMed  Google Scholar 

  55. Yashiro M, Hasegawa T, Fukuoka T, Kinoshita H, Morisaki T, Kasashima H, Masuda G, Kubo N, Hirakawa K (2014) The stemness of gastric cancer stem cells is sustained by TGFβ produced from cancer-associated fibroblasts. AACR. Cancer Res 7:3863

    Google Scholar 

  56. Sirkisoon SR, Carpenter RL, Rimkus T, Doheny D, Zhu D, Aguayo NR, Xing F, Chan M, Ruiz J, Metheny-Barlow LJ, Strowd R, Lin J, Regua AT, Arrigo A, Anguelov M, Pasche B, Debinski W, Watabe K, Lo HW (2020). TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment. Oncogene 39(1), 64–78

    Google Scholar 

  57. Schulz A, Meyer F, Dubrovska A, Borgmann K (2019) Cancer stem cells and radioresistance: DNA repair and beyond. Cancers (Basel) 11:862

    Article  CAS  Google Scholar 

  58. Dittmer J (2018) Breast cancer stem cells: features, key drivers and treatment options. Semin Cancer Biol 53:59–74

    Article  PubMed  Google Scholar 

  59. Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, Ma KW, Xia W, Cheung TT (2018) Blocking CDK1/PDK1/beta-catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics 8:3737–3750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gerweck LE, Wakimoto H (2016) At the crossroads of cancer stem cells, radiation biology, and radiation oncology. Cancer Res 76:994–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Baek SJ, Ishii H, Tamari K, Hayashi K, Nishida N, Konno M, Kawamoto K, Koseki J, Fukusumi T, Hasegawa S, Ogawa H, Hamabe A, Miyo M, Noguchi K, Seo Y, Doki Y, Mori M, Ogawa K (2015) Cancer stem cells: the potential of carbon ion beam radiation and new radiosensitizers (Review). Oncol Rep 34:2233–2237

    Article  CAS  PubMed  Google Scholar 

  62. Rajaee Z, Khoei S, Mahdavi SR, Ebrahimi M, Shirvalilou S, Mahdavian A (2018) Evaluation of the effect of hyperthermia and electron radiation on prostate cancer stem cells. Radiat Environ Biophys 57:133–142

    Article  PubMed  Google Scholar 

  63. Chikamatsu K, Ishii H, Murata T, Sakakura K, Shino M, Toyoda M, Takahashi K, Masuyama K (2013) Alteration of cancer stem cell-like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck. Cancer Sci 104:1468–1475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bertrand G, Maalouf M, Boivin A, Battiston-Montagne P, Beuve M, Levy A, Jalade P, Fournier C, Ardail D, Magne N, Alphonse G, Rodriguez-Lafrasse C (2014) Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev Rep 10:114–126

    Article  CAS  PubMed  Google Scholar 

  65. Ponnurangam S, Mammen JM, Ramalingam S, He Z, Zhang Y, Umar S, Subramaniam D, Anant S (2012) Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Mol Cancer Ther 11:963–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhu M, Chen S, Hua L, Zhang C, Chen M, Chen D, Dong Y, Zhang Y, Li M, Song X, Chen H, Zheng H (2017) Self-targeted salinomycin-loaded DSPE-PEG-methotrexate nanomicelles for targeting both head and neck squamous cell carcinoma cancer cells and cancer stem cells. Nanomedicine (Lond) 12:295–315

    Article  CAS  Google Scholar 

  67. Fiorillo M, Verre AF, Iliut M, Peiris-Pages M, Ozsvari B, Gandara R, Cappello AR, Sotgia F, Vijayaraghavan A, Lisanti MP (2015) Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”. Oncotarget 6:3553–3562

    Article  PubMed  PubMed Central  Google Scholar 

  68. Zhang Y, Wang SX, Ma JW, Li HY, Ye JC, Xie SM, Du B, Zhong XY (2015) EGCG inhibits properties of glioma stem-like cells and synergizes with temozolomide through downregulation of P-glycoprotein inhibition. J Neuro-Oncol 121:41–52

    Article  CAS  Google Scholar 

  69. Adorno-Cruz V, Kibria G, Liu X, Doherty M, Junk DJ, Guan D, Hubert C, Venere M, Mulkearns-Hubert E, Sinyuk M, Alvarado A, Caplan AI, Rich J, Gerson SL, Lathia J, Liu H (2015) Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance. Cancer Res 75:924–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Atashzar MRO, Baharlou R, Karami J, Abdollahi H, Rezaei R, Pourramezan F, Zoljalali Moghaddam SH (2020) Cancer stem cells: A review from origin to therapeutic implications. J Cell Physiology 235(2):790–803

    Google Scholar 

  71. Motegi A, Fujii S, Zenda S, Arahira S, Tahara M, Hayashi R, Akimoto T (2016) Impact of expression of CD44, a cancer stem cell marker, on the treatment outcomes of intensity modulated radiation therapy in patients with oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 94:461–468

    Article  CAS  PubMed  Google Scholar 

  72. Baharlou R, Tajik N, Behdani M, Shokrgozar MA, Tavana V, Kazemi-Lomedasht F, Faraji F, Habibi-Anbouhi M (2018) An antibody fragment against human delta-like ligand-4 for inhibition of cell proliferation and neovascularization. Immunopharmacol Immunotoxicol 40:368–374

    Article  CAS  PubMed  Google Scholar 

  73. Baharlou R, Tajik N, Habibi-Anbouhi M, Shokrgozar MA, Zarnani A-H, Shahhosseini F, Behdani M (2018) Generation and characterization of an anti-delta like ligand-4 Nanobody to induce non-productive angiogenesis. Anal Biochem 544:34–41

    Article  CAS  PubMed  Google Scholar 

  74. Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16:474–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhu X, Niedermann G (2015) Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. Onco Targets Ther 2:476–482

    Google Scholar 

  76. Balin AK, Fisher AJ, Carter DM (1984) Oxygen modulates growth of human cells at physiologic partial pressures. J Exp Med 160:152–166

    Article  CAS  PubMed  Google Scholar 

  77. Muller M, Mentel M, van Hellemond JJ, Henze K, Woehle C, Gould SB, Yu RY, van der Giezen M, Tielens AG, Martin WF (2012) Biochemistry and evolution of anaerobic energy metabolism in eukaryotes. Microbiol Mol Biol Rev 76:444–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Atteia A, van Lis R, Tielens AG, Martin WF (2013) Anaerobic energy metabolism in unicellular photosynthetic eukaryotes. Biochim Biophys Acta 1827:210–223

    Article  CAS  PubMed  Google Scholar 

  79. Zimorski V, Mentel M, Tielens AGM, Martin WF (2019) Energy metabolism in anaerobic eukaryotes and earth’s late oxygenation. Free Radic Biol Med 140:279–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226

    Article  CAS  PubMed  Google Scholar 

  81. Xing F, Okuda H, Watabe M, Kobayashi A, Pai SK, Liu W, Pandey PR, Fukuda K, Hirota S, Sugai T, Wakabayshi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Mo YY, Watabe K (2011) Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30:4075–4086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nantajit D, Lin D, Li JJ (2015) The network of epithelial–mesenchymal transition: potential new targets for tumor resistance. J Cancer Res Clin Oncol 141:1697–1713

    Article  CAS  PubMed  Google Scholar 

  83. Hall EJ, Giaccia AJ (2012) Oxygen effect and reoxygenation. Chapter 6. Lippincott Williams & Wolters Kluwer, Philadelphia

    Google Scholar 

  84. Miyagi Y, Zhang H, Wheeler KT (1997) Radiation-induced DNA damage in tumors and normal tissues: IV. Influence of proliferation status and cell type on the formation of oxygen-dependent DNA damage in cultured cells. Radiat Res 148:29–34

    Article  CAS  PubMed  Google Scholar 

  85. Brown JM, Giaccia AJ (1994) Tumour hypoxia: the picture has changed in the 1990s. Int J Radiat Biol 65:95–102

    Article  CAS  PubMed  Google Scholar 

  86. Dang CV (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. McGarry RC, Papiez L, Williams M, Whitford T, Timmerman RD (2005) Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: phase I study. Int J Radiat Oncol Biol Phys 63:1010–1015

    Article  PubMed  Google Scholar 

  88. Brown JM, Carlson DJ, Brenner DJ (2014) The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int J Radiat Oncol Biol Phys 88:254–262

    Article  PubMed  PubMed Central  Google Scholar 

  89. Lindblom EK, Dasu A, Toma-Dasu I (2019) Hypoxia induced by vascular damage at high doses could compromise the outcome of radiotherapy. Anticancer Res 39:2337–2340

    Article  CAS  PubMed  Google Scholar 

  90. Song CW, Griffin RJ, Lee YJ, Cho H, Seo J, Park I, Kim HK, Kim DH, Kim MS, Dusenbery KE, Cho LC (2019) Reoxygenation and repopulation of tumor cells after ablative hypofractionated radiotherapy (SBRT and SRS) in murine tumors. Radiat Res 192(2):159–168

    Article  CAS  PubMed  Google Scholar 

  91. Tong Q, Weaver MR, Kosmacek EA, O’Connor BP, Harmacek L, Venkataraman S, Oberley-Deegan RE (2016) MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene. Free Radic Biol Med 94:185–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang H, Lu H, Xiang L, Bullen JW, Zhang C, Samanta D, Gilkes DM, He J, Semenza GL (2015) HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A 112:E6215–E6223

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Saito S, Lin YC, Tsai MH, Lin CS, Murayama Y, Sato R, Yokoyama KK (2015) Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J Med Sci 31:279–286

    Article  PubMed  Google Scholar 

  94. Semenza GL (2016) Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol Asp Med 47:15–23

    Google Scholar 

  95. Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN (2009) The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8:3274–3284

    Article  CAS  PubMed  Google Scholar 

  96. Liao J, Qian F, Tchabo N, Mhawech-Fauceglia P, Beck A, Qian Z, Wang X, Huss WJ, Lele SB, Morrison CD, Odunsi K (2014) Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One 9(1)

    Google Scholar 

  97. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5

    Article  CAS  PubMed  Google Scholar 

  99. Kim HM, Haraguchi N, Ishii H, Ohkuma M, Okano M, Mimori K, Eguchi H, Yamamoto H, Nagano H, Sekimoto M, Doki Y, Mori M (2012) Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann Surg Oncol 19(Suppl 3):S539–S548

    Article  PubMed  Google Scholar 

  100. Ryoo IG, Lee SH, Kwak MK (2016) Redox modulating NRF2: a potential mediator of cancer stem cell resistance. Oxidative Med Cell Longev 2016:2428153

    Article  CAS  Google Scholar 

  101. Ding S, Li C, Cheng N, Cui X, Xu X, Zhou G (2015) Redox regulation in cancer stem cells. Oxidative Med Cell Longev 2015:750798

    Article  Google Scholar 

  102. Vitale I, Manic G, Dandrea V, De Maria R (2015) Role of autophagy in the maintenance and function of cancer stem cells. Int J Dev Biol 59:95–108

    Article  CAS  PubMed  Google Scholar 

  103. Nagano O, Okazaki S, Saya H (2013) Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene 32:5191–5198

    Article  CAS  PubMed  Google Scholar 

  104. Ullmann P, Nurmik M, Begaj R, Haan S, Letellier E (2019) Hypoxia- and MicroRNA-induced metabolic reprogramming of tumor-initiating cells. Cells 8:528

    Article  CAS  PubMed Central  Google Scholar 

  105. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

    Article  CAS  PubMed  Google Scholar 

  106. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lee KE, Simon MC (2012) From stem cells to cancer stem cells: HIF takes the stage. Curr Opin Cell Biol 24:232–235

    Article  CAS  PubMed  Google Scholar 

  108. Fluegen G, Avivar-Valderas A, Wang Y, Padgen MR, Williams JK, Nobre AR, Calvo V, Cheung JF, Bravo-Cordero JJ, Entenberg D, Castracane J, Verkhusha V, Keely PJ, Condeelis J, Aguirre-Ghiso JA (2017) Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nat Cell Biol 19:120–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Carcereri de Prati A, Butturini E, Rigo A, Oppici E, Rossin M, Boriero D, Mariotto S (2017) Metastatic breast Cancer cells enter into dormant state and express cancer stem cells phenotype under chronic hypoxia. J Cell Biochem 118:3237–3248

    Article  CAS  PubMed  Google Scholar 

  110. Endo H, Okuyama H, Ohue M, Inoue M (2014) Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia. PLoS One 9:e98858

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Naumov GN, Townson JL, MacDonald IC, Wilson SM, Bramwell VH, Groom AC, Chambers AF (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82:199–206

    Article  CAS  PubMed  Google Scholar 

  112. Demicheli R, Miceli R, Moliterni A, Zambetti M, Hrushesky WJ, Retsky MW, Valagussa P, Bonadonna G (2005) Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol 16:1449–1457

    Article  CAS  PubMed  Google Scholar 

  113. Daynac M, Chicheportiche A, Pineda JR, Gauthier LR, Boussin FD, Mouthon MA (2013) Quiescent neural stem cells exit dormancy upon alteration of GABAAR signaling following radiation damage. Stem Cell Res 11:516–528

    Article  CAS  PubMed  Google Scholar 

  114. Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, Merkel AR, Johnson JR, Sterling JA, Wu JY, Giaccia AJ (2016) Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 18:1078–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109:2784–2789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Smilowitz HM, Micca PL, Sasso D, Wu Q, Dyment N, Xue C, Kuo L (2016) Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma. Cancer Immunol Immunother 65:127–139

    Article  CAS  PubMed  Google Scholar 

  117. Marx V (2018) How to pull the blanket off dormant cancer cells. Nat Methods 15:249–252

    Article  CAS  PubMed  Google Scholar 

  118. Herman TS, Teicher BA, Holden SA, Collins LS (1989) Interaction of hyperthermia and radiation in murine cells: hypoxia and acidosis in vitro, tumor subpopulations in vivo. Cancer Res 49:3338–3343

    CAS  PubMed  Google Scholar 

  119. Kim IH, Lemmon MJ, Brown JM (1993) The influence of irradiation of the tumor bed on tumor hypoxia: measurements by radiation response, oxygen electrodes, and nitroimidazole binding. Radiat Res 135:411–417

    Article  CAS  PubMed  Google Scholar 

  120. Grimes DR, Kannan P, McIntyre A, Kavanagh A, Siddiky A, Wigfield S, Harris A, Partridge M (2016) The role of oxygen in avascular tumor growth. PLoS One 11:e0153692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J (2012) Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol 9:674–687

    Article  CAS  PubMed  Google Scholar 

  122. Campbell A, Davis LM, Wilkinson SK, Hesketh RL (2019) Emerging functional imaging biomarkers of tumour responses to radiotherapy. Cancers (Basel) 11:131

    Article  CAS  Google Scholar 

  123. Kakkad S, Krishnamachary B, Jacob D, Pacheco-Torres J, Goggins E, Bharti SK, Penet MF, Bhujwalla ZM (2019) Molecular and functional imaging insights into the role of hypoxia in cancer aggression. Cancer Metastasis Rev 38:51–64

    Article  PubMed  PubMed Central  Google Scholar 

  124. White DA, Zhang Z, Li L, Gerberich J, Stojadinovic S, Peschke P, Mason RP (2016) Developing oxygen-enhanced magnetic resonance imaging as a prognostic biomarker of radiation response. Cancer Lett 380:69–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kjellsson Lindblom E, Ureba A, Dasu A, Wersall P, Even AJG, van Elmpt W, Lambin P, Toma-Dasu I (2019) Impact of SBRT fractionation in hypoxia dose painting – accounting for heterogeneous and dynamic tumor oxygenation. Med Phys 46:2512–2521

    Article  CAS  PubMed  Google Scholar 

  126. Brown JM (1982) The mechanisms of cytotoxicity and chemosensitization by misonidazole and other nitroimidazoles. Int J Radiat Oncol Biol Phys 8:675–682

    Article  CAS  PubMed  Google Scholar 

  127. Lin A, Maity A (2015) Molecular pathways: a novel approach to targeting hypoxia and improving radiotherapy efficacy via reduction in oxygen demand. Clin Cancer Res 21:1995–2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Marcial VA, Pajak TF, Kramer S, Davis LW, Stetz J, Laramore GE, Jacobs JR, Al-Sarraf M, Brady LW (1988) Radiation therapy oncology group (RTOG) studies in head and neck cancer. Semin Oncol 15:39–60

    CAS  PubMed  Google Scholar 

  129. Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, Glicksman R, Chaib S, Zamiara P, Milosevic M, Wouters BG, Bristow RG, Koritzinsky M (2013) Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res 19:6741–6750

    Article  CAS  PubMed  Google Scholar 

  130. Secomb TW, Hsu R, Dewhirst MW (2004) Synergistic effects of hyperoxic gas breathing and reduced oxygen consumption on tumor oxygenation: a theoretical model. Int J Radiat Oncol Biol Phys 59:572–578

    Article  CAS  PubMed  Google Scholar 

  131. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393

    Article  CAS  PubMed  Google Scholar 

  132. Koritzinsky M (2015) Metformin: a novel biological modifier of tumor response to radiation therapy. Int J Radiat Oncol Biol Phys 93:454–464

    Article  CAS  PubMed  Google Scholar 

  133. Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (2015) Pericytes at the intersection between tissue regeneration and pathology. Clin Sci (Lond) 128:81–93

    Article  CAS  Google Scholar 

  136. Ribeiro AL, Okamoto OK (2015) Combined effects of pericytes in the tumor microenvironment. Stem Cells Int 2015:868475–868475

    Article  PubMed  PubMed Central  Google Scholar 

  137. Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307:C25–C38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jani A, Shaikh F, Barton S, Willis C, Banerjee D, Mitchell J, Hernandez SL, Hei T, Kadenhe-Chiweshe A, Yamashiro DJ, Connolly EP (2016) High-dose, single-fraction irradiation rapidly reduces tumor vasculature and perfusion in a xenograft model of neuroblastoma. Int J Radiat Oncol Biol Phys 94:1173–1180

    Article  PubMed  Google Scholar 

  139. Wang HH, Cui YL, Zaorsky NG, Lan J, Deng L, Zeng XL, Wu ZQ, Tao Z, Guo WH, Wang QX, Zhao LJ, Yuan ZY, Lu Y, Wang P, Meng MB (2016) Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy. Cancer Lett 375:349–359

    Article  CAS  PubMed  Google Scholar 

  140. Hamdan R, Zhou Z, Kleinerman ES (2014) Blocking SDF-1alpha/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors. Mol Cancer Ther 13:483–491

    Article  CAS  PubMed  Google Scholar 

  141. Dang CV (2012) Links between metabolism and cancer. Genes Dev 26:877–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Martin-Castillo B, Menendez JA (2010) Metformin and energy metabolism in breast cancer: from insulin physiology to tumour-initiating stem cells. Curr Mol Med 10:674–691

    Article  CAS  PubMed  Google Scholar 

  143. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233

    Article  CAS  PubMed  Google Scholar 

  144. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, Shan C, Dai Q, Zhang L, Xie J, Gu TL, Jin P, Aleckovic M, LeRoy G, Kang Y, Sudderth JA, DeBerardinis RJ, Luan CH, Chen GZ, Muller S et al (2012) Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22:585–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329:1492–1499

    Article  CAS  PubMed  Google Scholar 

  146. Pasto A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, Amadori A (2014) Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 5:4305–4319

    Article  PubMed  PubMed Central  Google Scholar 

  147. Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L (2018) Mitochondrial metabolism and cancer. Cell Res 28:265–280

    Article  CAS  PubMed  Google Scholar 

  148. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, Somlo G, Jandial R, Ann D, Hanash S, Jove R, Yu H (2018) JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 27:1357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Weinhouse S, Millington RH, Wenner CE (1951) Metabolism of neoplastic tissue. I. The oxidation of carbohydrate and fatty acids in transplanted tumors. Cancer Res 11:845–850

    CAS  PubMed  Google Scholar 

  150. Wenner CE, Spirtes MA, Weinhouse S (1952) Metabolism of neoplastic tissue. II. A survey of enzymes of the citric acid cycle in transplanted tumors. Cancer Res 12:44–49

    CAS  PubMed  Google Scholar 

  151. Villa AM, Doglia SM (2004) Mitochondria in tumor cells studied by laser scanning confocal microscopy. J Biomed Opt 9:385–394

    Article  CAS  PubMed  Google Scholar 

  152. Li JJ, Oberley LW, St Clair DK, Ridnour LA, Oberley TD (1995) Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase. Oncogene 10:1989–2000

    CAS  PubMed  Google Scholar 

  153. Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, Baudy AR, Hatzivassiliou G, Evangelista M, Settleman J (2016) mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell 29:548–562

    Article  CAS  PubMed  Google Scholar 

  154. Rodriguez-Enriquez S, Marin-Hernandez A, Gallardo-Perez JC, Carreno-Fuentes L, Moreno-Sanchez R (2009) Targeting of cancer energy metabolism. Mol Nutr Food Res 53:29–48

    Article  CAS  PubMed  Google Scholar 

  155. Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Pavlides S, Tsirigos A, Ertel A, Pestell RG, Broda P, Minetti C, Lisanti MP, Sotgia F (2011) Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 10:4047–4064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, Fletcher-Sananikone E, Colla S, Wang YA, Chin L, Depinho RA (2010) Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468:701–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, Schafer ZT, Evans RM, Suda T, Lee CH, Pandolfi PP (2012) A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 18:1350–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Knobloch M, Braun SM, Zurkirchen L, von Schoultz C, Zamboni N, Arauzo-Bravo MJ, Kovacs WJ, Karalay O, Suter U, Machado RA, Roccio M, Lutolf MP, Semenkovich CF, Jessberger S (2013) Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493:226–230

    Article  CAS  PubMed  Google Scholar 

  159. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M (2010) Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 120:142–156

    Article  CAS  PubMed  Google Scholar 

  160. Candas D, Lu CL, Fan M, Chuang FY, Sweeney C, Borowsky AD, Li JJ (2014) Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Res 74:7498–7509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA (2005) Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105:1851–1861

    Article  CAS  PubMed  Google Scholar 

  162. Smolkova K, Plecita-Hlavata L, Bellance N, Benard G, Rossignol R, Jezek P (2011) Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 43(7):950–968

    Google Scholar 

  163. Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR, Vokes NI, Feist AM, Vander Heiden MG, Metallo CM (2014) Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell 55:253–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337

    Article  CAS  PubMed  Google Scholar 

  165. Metallo CM, Vander Heiden MG (2013) Understanding metabolic regulation and its influence on cell physiology. Mol Cell 49:388–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21:297–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and Cancer. Cell 166:555–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Oberley LW, McCormick ML, Sierra-Rivera E, Kasemset-St Clair D (1989) Manganese superoxide dismutase in normal and transformed human embryonic lung fibroblasts. Free Radic Biol Med 6:379–384

    Article  CAS  PubMed  Google Scholar 

  170. St Clair DK, Holland JC (1991) Complementary DNA encoding human colon cancer manganese superoxide dismutase and the expression of its gene in human cells. Cancer Res 51:939–943

    CAS  PubMed  Google Scholar 

  171. Dreier A, Barth S, Goswami A, Weis J (2012) Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance? Tumour Biol 33:85–94

    Article  CAS  PubMed  Google Scholar 

  172. Kulikov AV, Vdovin AS, Zhivotovsky B, Gogvadze V (2014) Targeting mitochondria by alpha-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment. Cell Mol Life Sci 71:2325–2333

    Article  CAS  PubMed  Google Scholar 

  173. Duru N, Candas D, Jiang G, Li JJ (2014) Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 140:1–14

    Article  CAS  PubMed  Google Scholar 

  174. Duru N, Fan M, Candas D, Menaa C, Liu H-C, Nantajit D, Wen Y, Xiao K, Eldridge A, Chromy BA (2012) HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin Cancer Res 18:6634–6647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lu CL, Qin L, Liu HC, Candas D, Fan M, Li JJ (2015) Tumor cells switch to mitochondrial oxidative phosphorylation under radiation via mTOR-mediated hexokinase II inhibition – a Warburg-reversing effect. PLoS One 10:e0121046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Obre E, Rossignol R (2015) Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 59:167–181

    Article  CAS  PubMed  Google Scholar 

  177. Chae YC, Caino MC, Lisanti S, Ghosh JC, Dohi T, Danial NN, Villanueva J, Ferrero S, Vaira V, Santambrogio L, Bosari S, Languino LR, Herlyn M, Altieri DC (2012) Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell 22:331–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kang R, Tang D, Schapiro NE, Loux T, Livesey KM, Billiar TR, Wang H, Van Houten B, Lotze MT, Zeh HJ (2014) The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene 33:567–577

    Article  CAS  PubMed  Google Scholar 

  179. Murley JS, Nantajit D, Baker KL, Kataoka Y, Li JJ, Grdina DJ (2008) Maintenance of manganese superoxide dismutase (SOD2)-mediated delayed radioprotection induced by repeated administration of the free thiol form of amifostine. Radiat Res 169:495–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Connor KM, Hempel N, Nelson KK, Dabiri G, Gamarra A, Belarmino J, Van De Water L, Mian BM, Melendez JA (2007) Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells. Cancer Res 67:10260–10267

    Article  CAS  PubMed  Google Scholar 

  181. Hempel N, Carrico PM, Melendez JA (2011) Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti Cancer Agents Med Chem 11:191–201

    Article  CAS  Google Scholar 

  182. Holley AK, Kiningham KK, Spitz DR, Edwards DP, Jenkins JT, Moore MR (2009) Progestin stimulation of manganese superoxide dismutase and invasive properties in T47D human breast cancer cells. J Steroid Biochem Mol Biol 117:23–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Nelson KK, Ranganathan AC, Mansouri J, Rodriguez AM, Providence KM, Rutter JL, Pumiglia K, Bennett JA, Melendez JA (2003) Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clin Cancer Res 9:424–432

    CAS  PubMed  Google Scholar 

  184. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, Derecka M, Chen Q, Hu Y, Sisler J, Hamed H, Lesnefsky EJ, Valerie K, Dent P, Larner AC (2013) Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem 288:31280–31288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Park JH, Vithayathil S, Kumar S, Sung PL, Dobrolecki LE, Putluri V, Bhat VB, Bhowmik SK, Gupta V, Arora K, Wu D, Tsouko E, Zhang Y, Maity S, Donti TR, Graham BH, Frigo DE, Coarfa C, Yotnda P, Putluri N et al (2016) Fatty acid oxidation-driven Src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep 14:2154–2165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, Berenguer A, Prats N, Toll A, Hueto JA, Bescos C, Di Croce L, Benitah SA (2017) Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541:41–45

    Article  CAS  PubMed  Google Scholar 

  187. LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16(992–1003):1001–1015

    Google Scholar 

  188. Caino MC, Ghosh JC, Chae YC, Vaira V, Rivadeneira DB, Faversani A, Rampini P, Kossenkov AV, Aird KM, Zhang R, Webster MR, Weeraratna AT, Bosari S, Languino LR, Altieri DC (2015) PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc Natl Acad Sci U S A 112:8638–8643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Wang Z, Fan M, Candas D, Zhang TQ, Qin L, Eldridge A, Wachsmann-Hogiu S, Ahmed KM, Chromy BA, Nantajit D, Duru N, He F, Chen M, Finkel T, Weinstein LS, Li JJ (2014) Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression. Dev Cell 29:217–232

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Qin L, Fan M, Candas D, Jiang G, Papadopoulos S, Tian L, Woloschak G, Grdina DJ, Li JJ (2015) CDK1 enhances mitochondrial bioenergetics for radiation-induced DNA repair. Cell Rep 13:2056–2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Candas D, Fan M, Nantajit D, Vaughan AT, Murley JS, Woloschak GE, Grdina DJ, Li JJ (2013) CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress. J Mol Cell Biol 5:166–175

    Article  CAS  PubMed  Google Scholar 

  192. Jin C, Qin L, Shi Y, Candas D, Fan M, Lu CL, Vaughan AT, Shen R, Wu LS, Liu R, Li RF, Murley JS, Woloschak G, Grdina DJ, Li JJ (2015) CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection. Free Radic Biol Med 81:77–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Liu R, Fan M, Candas D, Qin L, Zhang X, Eldridge A, Zou JX, Zhang T, Juma S, Jin C, Li RF, Perks J, Sun LQ, Vaughan AT, Hai CX, Gius DR, Li JJ (2015) CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor Radioresistance. Mol Cancer Ther 14:2090–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Nantajit D, Fan M, Duru N, Wen Y, Reed JC, Li JJ (2010) Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. PLoS One 5:e12341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Strack S, Wilson TJ, Cribbs JT (2013) Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules. J Cell Biol 201:1037–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282:11521–11529

    Article  CAS  PubMed  Google Scholar 

  197. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777

    Article  CAS  PubMed  Google Scholar 

  198. Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K (2013) Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res 52:585–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ackerman D, Simon MC (2014) Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol 24:472–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. de Padua MC, Delodi G, Vučetić M, Durivault J, Vial V, Bayer P, Rodrigues Noleto G, Mazure NM, Ždralević M, Pouysségur J (2017) Disrupting glucose-6-phosphate isomerase fully suppresses the “Warburg effect” and activates OXPHOS with minimal impact on tumor growth except in hypoxia. Oncotarget 8:87623

    Article  PubMed  PubMed Central  Google Scholar 

  201. Sormendi S, Wielockx B (2018) Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front Immunol 9:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Chambers AM, Wang J, Lupo KB, Yu H, Atallah Lanman NM, Matosevic S (2018) Adenosinergic signaling alters natural killer cell functional responses. Front Immunol 9:2533

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862–870

    Article  PubMed  Google Scholar 

  204. Kingsley DP (1975) An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol 48:863–866

    Article  CAS  PubMed  Google Scholar 

  205. Raventos A (1954) An abscopal effect of x-ray upon mouse spleen weight. Radiat Res 1:381–387

    Article  CAS  PubMed  Google Scholar 

  206. Mole RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol 26:234–241

    Article  CAS  PubMed  Google Scholar 

  207. Derer A, Deloch L, Rubner Y, Fietkau R, Frey B, Gaipl US (2015) Radio-immunotherapy-induced immunogenic cancer cells as basis for induction of systemic anti-tumor immune responses – pre-clinical evidence and ongoing clinical applications. Front Immunol 6:505

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Liang H, Deng L, Chmura S, Burnette B, Liadis N, Darga T, Beckett MA, Lingen MW, Witt M, Weichselbaum RR, Fu YX (2013) Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing. J Immunol 190:5874–5881

    Article  CAS  PubMed  Google Scholar 

  209. Formenti SC, Demaria S (2012) Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys 84:879–880

    Article  PubMed  Google Scholar 

  210. Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC (2015) Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 16:795–803

    Article  CAS  PubMed  Google Scholar 

  211. Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, Vanpouille-Box C, Friedman K, Ferrari de Andrade L, Wucherpfennig KW, Heguy A, Imai N, Gnjatic S, Emerson RO, Zhou XK, Zhang T, Chachoua A, Demaria S (2018) Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 24:1845–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Barker HE, Paget JT, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW (2014) Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5:403–416

    Article  PubMed  Google Scholar 

  214. Hu ZI, McArthur HL, Ho AY (2017) The Abscopal effect of radiation therapy: what is it and How can we use it in breast cancer? Curr Breast Cancer Rep 9:45–51

    Article  PubMed  PubMed Central  Google Scholar 

  215. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T, Huang X, Gajewski TF, Chen ZJ, Fu YX, Weichselbaum RR (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P (2013) Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602

    Article  CAS  PubMed  Google Scholar 

  218. Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Davoli T, Uno H, Wooten EC, Elledge SJ (2017) Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355:eaaf8399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Hallahan DE, Geng L, Cmelak AJ, Chakravarthy AB, Martin W, Scarfone C, Gonzalez A (2001) Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature. J Control Release 74:183–191

    Article  CAS  PubMed  Google Scholar 

  221. Corso CD, Ali AN, Diaz R (2011) Radiation-induced tumor neoantigens: imaging and therapeutic implications. Am J Cancer Res 1:390–412

    PubMed  PubMed Central  Google Scholar 

  222. Lhuillier C, Rudqvist NP, Elemento O, Formenti SC, Demaria S (2019) Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system. Genome Med 11:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348:69–74

    Article  CAS  PubMed  Google Scholar 

  224. Song KH, Jung SY, Kang SM, Kim MH, Ahn J, Hwang SG, Lee JH, Lim DS, Nam SY, Song JY (2016) Induction of immunogenic cell death by radiation-upregulated karyopherin alpha 2 in vitro. Eur J Cell Biol 95:219–227

    Article  CAS  PubMed  Google Scholar 

  225. Liepe J, Marino F, Sidney J, Jeko A, Bunting DE, Sette A, Kloetzel PM, Stumpf MP, Heck AJ, Mishto M (2016) A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354:354–358

    Article  CAS  PubMed  Google Scholar 

  226. Sharma A, Bode B, Wenger RH, Lehmann K, Sartori AA, Moch H, Knuth A, Boehmer L, Broek M (2011) Gamma-radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo. PLoS One 6:e28217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Andersen MH, Bonfill JE, Neisig A, Arsequell G, Søndergaard I, Neefjes J, Zeuthen J, Elliott T, Haurum JS (1999) Phosphorylated peptides can be transported by TAP molecules, presented by class I MHC molecules, and recognized by phosphopeptide-specific CTL. J Immunol 163:3812–3818

    CAS  PubMed  Google Scholar 

  228. Haurum JS, Høier IB, Arsequell G, Neisig A, Valencia G, Zeuthen J, Neefjes J, Elliott T (1999) Presentation of cytosolic glycosylated peptides by human class I major histocompatibility complex molecules in vivo. J Exp Med 190:145–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Cobbold M, De La Peña H, Norris A, Polefrone JM, Qian J, English AM, Cummings KL, Penny S, Turner JE, Cottine J (2013) MHC class I–associated phosphopeptides are the targets of memory-like immunity in leukemia. Sci Transl Med 5:203ra125–203ra125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Neefjes J, Ovaa H (2013) A peptide’s perspective on antigen presentation to the immune system. Nat Chem Biol 9:769

    Article  CAS  PubMed  Google Scholar 

  231. Zarling AL, Polefrone JM, Evans AM, Mikesh LM, Shabanowitz J, Lewis ST, Engelhard VH, Hunt DF (2006) Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy. Proc Natl Acad Sci 103:14889–14894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Abdel-Wahab Z, Dar MM, Hester D, Vervaert C, Gangavalli R, Barber J, Darrow TL, Seigler HF (1996) Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells. Cell Immunol 171:246–254

    CAS  PubMed  Google Scholar 

  234. Sharma A, Bode B, Studer G, Moch H, Okoniewski M, Knuth A, von Boehmer L, van den Broek M (2013) Radiotherapy of human sarcoma promotes an intratumoral immune effector signature. Clin Cancer Res 19:4843–4853

    Article  CAS  PubMed  Google Scholar 

  235. Luo N, Nixon MJ, Gonzalez-Ericsson PI, Sanchez V, Opalenik SR, Li H, Zahnow CA, Nickels ML, Liu F, Tantawy MN, Sanders ME, Manning HC, Balko JM (2018) DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 9:248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Paulson KG, Tegeder A, Willmes C, Iyer JG, Afanasiev OK, Schrama D, Koba S, Thibodeau R, Nagase K, Simonson WT, Seo A, Koelle DM, Madeleine M, Bhatia S, Nakajima H, Sano S, Hardwick JS, Disis ML, Cleary MA, Becker JC et al (2014) Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol Res 2:1071–1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Dillon MT, Bergerhoff KF, Pedersen M, Whittock H, Crespo-Rodriguez E, Patin EC, Pearson A, Smith HG, Paget JTE, Patel RR, Foo S, Bozhanova G, Ragulan C, Fontana E, Desai K, Wilkins AC, Sadanandam A, Melcher A, McLaughlin M, Harrington KJ (2019) ATR inhibition potentiates the radiation-induced inflammatory tumor microenvironment. Clin Cancer Res 25:3392–3403

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Stern LJ, Santambrogio L (2016) The melting pot of the MHC II peptidome. Curr Opin Immunol 40:70–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Farooque A, Singh N, Adhikari JS, Afrin F, Dwarakanath BS (2014) Enhanced antitumor immunity contributes to the radio-sensitization of ehrlich ascites tumor by the glycolytic inhibitor 2-deoxy-D-glucose in mice. PLoS One 9:e108131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Frey B, Ruckert M, Weber J, Mayr X, Derer A, Lotter M, Bert C, Rodel F, Fietkau R, Gaipl US (2017) Hypofractionated irradiation has immune stimulatory potential and induces a timely restricted infiltration of immune cells in colon cancer tumors. Front Immunol 8:231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Depontieu FR, Qian J, Zarling AL, McMiller TL, Salay TM, Norris A, English AM, Shabanowitz J, Engelhard VH, Hunt DF, Topalian SL (2009) Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy. Proc Natl Acad Sci 106:12073–12078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ (2004) An antigenic peptide produced by peptide splicing in the proteasome. Science 304:587–590

    Article  CAS  PubMed  Google Scholar 

  243. Dalet A, Robbins PF, Stroobant V, Vigneron N, Li YF, El-Gamil M, Hanada K-I, Yang JC, Rosenberg SA, Van den Eynde BJ (2011) An antigenic peptide produced by reverse splicing and double asparagine deamidation. Proc Natl Acad Sci 108:E323–E331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M, Diekmann J, Boegel S, Schrors B, Vascotto F, Castle JC, Tadmor AD, Schoenberger SP, Huber C, Tureci O, Sahin U (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I et al (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Couture A, Garnier A, Docagne F, Boyer O, Vivien D, Le-Mauff B, Latouche JB, Toutirais O (2019) HLA-class II artificial antigen presenting cells in CD4(+) T cell-based immunotherapy. Front Immunol 10:1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Rhodes KR, Green JJ (2018) Nanoscale artificial antigen presenting cells for cancer immunotherapy. Mol Immunol 98:13–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204:49–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Vanpouille-Box C, Pilones KA, Wennerberg E, Formenti SC, Demaria S (2015) In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 33:7415–7422

    Article  PubMed  PubMed Central  Google Scholar 

  250. Belcaid Z, Phallen JA, Zeng J, See AP, Mathios D, Gottschalk C, Nicholas S, Kellett M, Ruzevick J, Jackson C, Albesiano E, Durham NM, Ye X, Tran PT, Tyler B, Wong JW, Brem H, Pardoll DM, Drake CG, Lim M (2014) Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One 9:e101764

    Article  PubMed  PubMed Central  Google Scholar 

  251. Vanpouille-Box C, Formenti SC, Demaria S (2018) Toward precision radiotherapy for use with immune checkpoint blockers. Clin Cancer Res 24:259–265

    Article  CAS  PubMed  Google Scholar 

  252. Wennerberg E, Lhuillier C, Vanpouille-Box C, Pilones KA, Garcia-Martinez E, Rudqvist NP, Formenti SC, Demaria S (2017) Barriers to radiation-induced in situ tumor vaccination. Front Immunol 8:229

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  253. Torihata H, Ishikawa F, Okada Y, Tanaka Y, Uchida T, Suguro T, Kakiuchi T (2004) Irradiation up-regulates CD80 expression through two different mechanisms in spleen B cells, B lymphoma cells, and dendritic cells. Immunology 112:219–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Liu S-Z, Jin S-Z, Liu X-D, Sun Y-M (2001) Role of CD28/B7 costimulation and IL-12/IL-10 interaction in the radiation-induced immune changes. BMC Immunol 2:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Shen X, Zhang L, Li J, Li Y, Wang Y, Xu Z-X (2019) Recent findings in the regulation of programmed death ligand 1 expression. Front Immunol 10:1337–1337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Muenst S, Soysal SD, Tzankov A, Hoeller S (2015) The PD-1/PD-L1 pathway: biological background and clinical relevance of an emerging treatment target in immunotherapy. Expert Opin Ther Targets 19:201–211

    Article  CAS  PubMed  Google Scholar 

  258. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:1537–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Tsai HF, Hsu PN (2017) Cancer immunotherapy by targeting immune checkpoints: mechanism of T cell dysfunction in cancer immunity and new therapeutic targets. J Biomed Sci 24:35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  260. D’Arrigo P, Russo M, Rea A, Tufano M, Guadagno E, Del Basso De Caro ML, Pacelli R, Hausch F, Staibano S, Ilardi G, Parisi S, Romano MF, Romano S (2017) A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma. Oncotarget 8:68291–68304

    Article  PubMed  PubMed Central  Google Scholar 

  261. Skinner HD, Giri U, Yang LP, Kumar M, Liu Y, Story MD, Pickering CR, Byers LA, Williams MD, Wang J, Shen L, Yoo SY, Fan YH, Molkentine DP, Beadle BM, Meyn RE, Myers JN, Heymach JV (2017) Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer. Clin Cancer Res 23:2713–2722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Ishibashi M, Tamura H, Sunakawa M, Kondo-Onodera A, Okuyama N, Hamada Y, Moriya K, Choi I, Tamada K, Inokuchi K (2016) Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunol Res 4:779–788

    Article  CAS  PubMed  Google Scholar 

  263. 2014. PD-L1 blockade maintains irradiation-mediated antitumor immunity. Cancer Discov 4:Of16

    Google Scholar 

  264. Zhang P, Liu J, Li W, Li S, Han X (2018) Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD-L1. Cancer Med 7:3178–3187

    Article  CAS  PubMed Central  Google Scholar 

  265. Jiang Z, Yang Y, Yang Y, Zhang Y, Yue Z, Pan Z, Ren X (2017) Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune. Biomed Pharmacother 96:378–383

    Article  CAS  PubMed  Google Scholar 

  266. Oweida A, Lennon S, Calame D, Korpela S, Bhatia S, Sharma J, Graham C, Binder D, Serkova N, Raben D, Heasley L, Clambey E, Nemenoff R, Karam SD (2017) Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Onco Targets Ther 6:e1356153–e1356153

    Google Scholar 

  267. Li D, Chen R, Wang YW, Fornace AJ Jr, Li HH (2018) Prior irradiation results in elevated programmed cell death protein 1 (PD-1) in T cells. Int J Radiat Biol 94:488–494

    Article  CAS  PubMed  Google Scholar 

  268. Chao MP, Majeti R, Weissman IL (2011) Programmed cell removal: a new obstacle in the road to developing cancer. Nat Rev Cancer 12:58–67

    Article  PubMed  CAS  Google Scholar 

  269. Gao AG, Lindberg FP, Finn MB, Blystone SD, Brown EJ, Frazier WA (1996) Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin. J Biol Chem 271:21–24

    Article  CAS  PubMed  Google Scholar 

  270. Liu Y, Merlin D, Burst SL, Pochet M, Madara JL, Parkos CA (2001) The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47. J Biol Chem 276:40156–40166

    Article  CAS  PubMed  Google Scholar 

  271. Lindberg FP, Bullard DC, Caver TE, Gresham HD, Beaudet AL, Brown EJ (1996) Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274:795–798

    Article  CAS  PubMed  Google Scholar 

  272. Miyashita M, Ohnishi H, Okazawa H, Tomonaga H, Hayashi A, Fujimoto TT, Furuya N, Matozaki T (2004) Promotion of neurite and filopodium formation by CD47: roles of integrins, Rac, and Cdc42. Mol Biol Cell 15:3950–3963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Reinhold MI, Lindberg FP, Kersh GJ, Allen PM, Brown EJ (1997) Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J Exp Med 185:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD (2009) Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci Transl Med 1:3ra7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  275. Maxhimer JB, Shih HB, Isenberg JS, Miller TW, Roberts DD (2009) Thrombospondin-1/CD47 blockade following ischemia-reperfusion injury is tissue protective. Plast Reconstr Surg 124:1880–1889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. McCracken MN, Cha AC, Weissman IL (2015) Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “Don’t eat me” signals. Clin Cancer Res 21:3597–3601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Soto-Pantoja DR, Terabe M, Ghosh A, Ridnour LA, DeGraff WG, Wink DA, Berzofsky JA, Roberts DD (2014) CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res 74:6771–6783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Menaa C, Fan M, Lu H-C, Alexandrou A, Juma S, Perks J, Li JJ (2013) The dynamic change of CD47 expression promotes tumor burden, metastases and resistance of breast cancer cells to radiotherapy. Cancer Res AACR Poster:4963

    Google Scholar 

  279. Soto-Pantoja DR, Miller TW, Pendrak ML, DeGraff WG, Sullivan C, Ridnour LA, Abu-Asab M, Wink DA, Tsokos M, Roberts DD (2012) CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8:1628–1642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Miller TW, Soto-Pantoja DR, Schwartz AL, Sipes JM, DeGraff WG, Ridnour LA, Wink DA, Roberts DD (2015) CD47 receptor globally regulates metabolic pathways that control resistance to ionizing radiation. J Biol Chem 290:24858–24874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Wu S, Zhang Q, Zhang F, Meng F, Liu S, Zhou R, Wu Q, Li X, Shen L, Huang J, Qin J, Ouyang S, Xia Z, Song H, Feng XH, Zou J, Xu P (2019) HER2 recruits AKT1 to disrupt STING signaling and suppress antiviral defense and antitumor immunity. Nat Cell Biol 21:1027–1040

    Article  CAS  PubMed  Google Scholar 

  282. Demaria S, Pilones KA, Vanpouille-Box C, Golden EB, Formenti SC (2014) The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res 182:170–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC (2014) Combinations of immunotherapy and radiation in cancer therapy. Front Oncol 4:325

    Article  PubMed  PubMed Central  Google Scholar 

  284. Munn DH, Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34:137–143

    Article  CAS  PubMed  Google Scholar 

  285. Monjazeb AM, Kent MS, Grossenbacher SK, Mall C, Zamora AE, Mirsoian A, Chen M, Kol A, Shiao SL, Reddy A, Perks JR, W, T.N.C, Sparger EE, Canter RJ, Sckisel GD, Murphy WJ (2016) Blocking Indolamine-2,3-dioxygenase rebound immune suppression boosts antitumor effects of radio-immunotherapy in murine models and spontaneous canine malignancies. Clin Cancer Res 22:4328–4340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Creelan BC, Antonia S, Bepler G, Garrett TJ, Simon GR, Soliman HH (2013) Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in stage III non-small cell lung cancer. Onco Targets Ther 2:e23428

    Google Scholar 

  287. Brooks ED, Chang JY (2019) Time to abandon single-site irradiation for inducing abscopal effects. Nat Rev Clin Oncol 16:123–135

    Article  PubMed  Google Scholar 

  288. Li A, Barsoumian HB, Schoenhals JE, Caetano MS, Wang X, Menon H, Valdecanas DR, Niknam S, Younes AI, Cortez MA, Welsh JW (2019) IDO1 inhibition overcomes radiation-induced “rebound immune suppression” by reducing numbers of IDO1-expressing myeloid-derived suppressor cells in the tumor microenvironment. Int J Radiat Oncol Biol Phys 104:903–912

    Article  CAS  PubMed  Google Scholar 

  289. Deng L, Liang H, Burnette B, Weicheslbaum RR, Fu YX (2014) Radiation and anti-PD-L1 antibody combinatorial therapy induce T cell-mediated depletion of myeloid-derived suppressor cells and tumor regression. Onco Targets Ther 3:e28499

    Google Scholar 

  290. Lan J, Li R, Yin LM, Deng L, Gui J, Chen BQ, Zhou L, Meng MB, Huang QR, Mo XM, Wei YQ, Lu B, Dicker A, Xue JX, Lu Y (2018) Targeting myeloid-derived suppressor cells and programmed death ligand 1 confers therapeutic advantage of ablative Hypofractionated radiation therapy compared with conventional fractionated radiation therapy. Int J Radiat Oncol Biol Phys 101:74–87

    Article  PubMed  Google Scholar 

  291. Wang SW, Sun YM (2014) The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncol 44:1032–1040

    Article  CAS  PubMed  Google Scholar 

  292. Yin Z, Ma T, Lin Y, Lu X, Zhang C, Chen S, Jian Z (2018) IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J Cell Biochem 119:9419–9432

    Article  CAS  PubMed  Google Scholar 

  293. Chiang CS, Fu SY, Wang SC, Yu CF, Chen FH, Lin CM, Hong JH (2012) Irradiation promotes an m2 macrophage phenotype in tumor hypoxia. Front Oncol 2:89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Leblond MM, Peres EA, Helaine C, Gerault AN, Moulin D, Anfray C, Divoux D, Petit E, Bernaudin M, Valable S (2017) M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma. Oncotarget 8:72597–72612

    Article  PubMed  PubMed Central  Google Scholar 

  295. Darragh LB, Oweida AJ, Karam SD (2018) Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor microenvironment. Front Immunol 9:3154

    Article  CAS  PubMed  Google Scholar 

  296. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, Portela Catani JP, Hannani D, Duret H, Steegh K, Martins I, Schlemmer F, Michaud M, Kepp O, Sukkurwala AQ, Menger L, Vacchelli E, Droin N, Galluzzi L, Krzysiek R et al (2013) Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38:729–741

    Article  CAS  PubMed  Google Scholar 

  297. Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC (2014) Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Onco Targets Ther 3:e28518

    Google Scholar 

  298. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL (2007) Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 117:1305–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Chatterjee A, Kosmacek EA, Oberley-Deegan RE (2017) MnTE-2-PyP treatment, or NOX4 inhibition, protects against radiation-induced damage in mouse primary prostate fibroblasts by inhibiting the TGF-Beta 1 signaling pathway. Radiat Res 187:367–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Chalmin F, Mignot G, Bruchard M, Chevriaux A, Vegran F, Hichami A, Ladoire S, Derangere V, Vincent J, Masson D, Robson SC, Eberl G, Pallandre JR, Borg C, Ryffel B, Apetoh L, Rebe C, Ghiringhelli F (2012) Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity 36:362–373

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We apologize to the authors whose publication could not be included in this chapter due to limited space. We acknowledge Dr. Ralph Weichselbaum at the University of Chicago and Dr. Yang-Xin Fu at the University of Texas Southwestern for their invaluable inputs and discussions on radiation-associated tumor immunoregulation.

Competing Interests

The authors declare no competing interest exists.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA

    Jie Huang & Jian Jian Li

  2. NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA

    Jian Jian Li

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  1. Jie Huang
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  2. Jian Jian Li
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Correspondence to Jian Jian Li .

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Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

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Huang, J., Li, J.J. (2020). Multiple Dynamics in Tumor Microenvironment Under Radiotherapy. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1263. Springer, Cham. https://doi.org/10.1007/978-3-030-44518-8_10

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