Current Protein & Peptide ScienceCurrent Protein & Peptide ScienceCurrent Protein & Peptide Science1389-20371875-5550Bentham Science64562110.2174/0113892037252820231114045234Life SciencesResearch ArticleHypoxia A Typical Target in Human Lung Cancer TherapyUllahAsmatinfo@benthamscience.netShehzadiSomiainfo@benthamscience.netUllahNajeebinfo@benthamscience.netNawazTouseefinfo@benthamscience.netIqbalHarooninfo@benthamscience.netAzizTariqinfo@benthamscience.netClinical Research Institute, Zhejiang Provincial People’s HospitalUniversity Institute of Medical Laboratory Technology, The University of LahoreKey Laboratory of Applied Surface and Colloid Chemistry, School of Chemistry and Chemical Engineering, Shaanxi Normal UniversityFaculty of Pharmacy, Gomal UniversityZhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences HangzhouSchool of Engineering, Westlake University0105202425537638511012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2037/article/view/645621

Lung cancer (LC) is the leading cause of cancer-related death globally. Comprehensive knowledge of the cellular and molecular etiology of LC is perilous for the development of active treatment approaches. Hypoxia in cancer is linked with malignancy, and its phenotype is implicated in the hypoxic reaction, which is being studied as a prospective cancer treatment target. The hypervascularization of the tumor is the main feature of human LC, and hypoxia is a major stimulator of neo-angiogenesis. It was seen that low oxygen levels in human LC are a critical aspect of this lethal illness. However, as there is a considerable body of literature espousing the presumed functional relevance of hypoxia in LC, the direct measurement of oxygen concentration in Human LC is yet to be determined. This narrative review aims to show the importance and as a future target for novel research studies that can lead to the perception of LC therapy in hypoxic malignancies.

Hypoxialung cancerHIF-1αoxygen measurementspositron emission tomographyneo-angiogenesis .Riaz, S.P.; Lüchtenborg, M.; Coupland, V.H.; Spicer, J.; Peake, M.D.; Møller, H. Trends in incidence of small cell lung cancer and all lung cancer. Lung Cancer, 2012, 75(3), 280-284. doi: 10.1016/j.lungcan.2011.08.004 PMID: 21893364Toschi, L.; Cappuzzo, F.; Jänne, P.A. Evolution and future perspectives in the treatment of locally advanced non-small cell lung cancer. Ann. Oncol., 2007, 18(Suppl. 9), ix150-ix155. doi: 10.1093/annonc/mdm311 PMID: 17631569Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338Thun, M.; Peto, R.; Boreham, J.; Lopez, A.D. Stages of the cigarette epidemic on entering its second century. Tob. Control, 2012, 21(2), 96-101. doi: 10.1136/tobaccocontrol-2011-050294 PMID: 22345230Sampsonas, F. State of the art molecular pharmacology, pathogenesis and epigenetics of 3 major cancers: Lung cancer, ovarian cancer, and gliomas. Curr. Mol. Pharmacol., 2021, 14(6), 1003. doi: 10.2174/187446721406211220154432 PMID: 35018882Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J. Thorac. Oncol., 2019, 14(10), 1732-1742. doi: 10.1016/j.jtho.2019.05.044 PMID: 31260833Pastorino, U.; Silva, M.; Sestini, S.; Sabia, F.; Boeri, M.; Cantarutti, A.; Sverzellati, N.; Sozzi, G.; Corrao, G.; Marchianò, A. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: New confirmation of lung cancer screening efficacy. Ann. Oncol., 2019, 30(7), 1162-1169. doi: 10.1093/annonc/mdz117 PMID: 30937431Novikova, S.E.; Kurbatov, L.K.; Zavialova, M.G.; Zgoda, V.G.; Archakov, A.I. Omics technologies in diagnostics of lung adenocarcinoma. Biomed. Khim., 2017, 63(3), 181-210. doi: 10.18097/PBMC20176303181 PMID: 28781253Reck, M.; Mok, T.S.K.; Nishio, M.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; Finley, G.; Lee, A.; Coleman, S.; Deng, Y.; Kowanetz, M.; Shankar, G.; Lin, W.; Socinski, M.A.; Reck, M.; Mok, T.S.K.; Nishio, M.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; Finley, G.; Lee, A.; Coleman, S.; Deng, Y.; Kowanetz, M.; Shankar, G.; Lin, W.; Socinski, M.A. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir. Med., 2019, 7(5), 387-401. doi: 10.1016/S2213-2600(19)30084-0 PMID: 30922878Carvalho, S.; Troost, E.G.C.; Bons, J.; Menheere, P.; Lambin, P.; Oberije, C. Prognostic value of blood-biomarkers related to hypoxia, inflammation, immune response and tumour load in non-small cell lung cancer – A survival model with external validation. Radiother. Oncol., 2016, 119(3), 487-494. doi: 10.1016/j.radonc.2016.04.024 PMID: 27139126Wang, Y.; Yang, J.; Liu, H.; Bi, J.R.; Liu, Y.; Chen, Y.Y.; Cao, J.Y.; Lu, Y.J. The association between osteopontin and survival in non-small-cell lung cancer patients: a meta-analysis of 13 cohorts. OncoTargets Ther., 2015, 8, 3513-3521. PMID: 26648743Ullah, A.; Leong, S.W.; Wang, J.; Wu, Q.; Ghauri, M.A.; Sarwar, A.; Su, Q.; Zhang, Y. Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer. Cell Death Dis., 2021, 12(5), 490. doi: 10.1038/s41419-021-03771-z PMID: 33990544İlie, M.; Mazure, N.M.; Hofman, V.; Ammadi, R.E.; Ortholan, C.; Bonnetaud, C.; Havet, K.; Venissac, N.; Mograbi, B.; Mouroux, J.; Pouysségur, J.; Hofman, P. High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br. J. Cancer, 2010, 102(11), 1627-1635. doi: 10.1038/sj.bjc.6605690 PMID: 20461082Lim, A.M.; Rischin, D.; Fisher, R.; Cao, H.; Kwok, K.; Truong, D.; McArthur, G.A.; Young, R.J.; Giaccia, A.; Peters, L.; Le, Q.T. Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin. Cancer Res., 2012, 18(1), 301-307. doi: 10.1158/1078-0432.CCR-11-2295 PMID: 22096023Overgaard, J.; Eriksen, J.G.; Nordsmark, M.; Alsner, J.; Horsman, M.R. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo- controlled trial. Lancet Oncol., 2005, 6(10), 757-764. doi: 10.1016/S1470-2045(05)70292-8 PMID: 16198981Kulshreshtha, R.; Ferracin, M.; Wojcik, S.E.; Garzon, R.; Alder, H.; Agosto-Perez, F.J.; Davuluri, R.; Liu, C.G.; Croce, C.M.; Negrini, M.; Calin, G.A.; Ivan, M. A microRNA signature of hypoxia. Mol. Cell. Biol., 2007, 27(5), 1859-1867. doi: 10.1128/MCB.01395-06 PMID: 17194750Grosso, S.; Doyen, J.; Parks, S.K.; Bertero, T.; Paye, A.; Cardinaud, B.; Gounon, P.; Lacas-Gervais, S.; Noël, A.; Pouysségur, J.; Barbry, P.; Mazure, N.M.; Mari, B. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis., 2013, 4(3), e544. doi: 10.1038/cddis.2013.71 PMID: 23492775Eilertsen, M.; Andersen, S.; Al-Saad, S.; Richardsen, E.; Stenvold, H.; Hald, S.M.; Al-Shibli, K.; Donnem, T.; Busund, L.T.; Bremnes, R.M. Positive prognostic impact of miR-210 in non-small cell lung cancer. Lung Cancer, 2014, 83(2), 272-278. doi: 10.1016/j.lungcan.2013.11.005 PMID: 24305009Osugi, J.; Kimura, Y.; Owada, Y.; Inoue, T.; Watanabe, Y.; Yamaura, T.; Fukuhara, M.; Muto, S.; Okabe, N.; Matsumura, Y.; Hasegawa, T.; Yonechi, A.; Hoshino, M.; Higuchi, M.; Shio, Y.; Suzuki, H.; Gotoh, M. Prognostic impact of hypoxia-inducible miRNA-210 in patients with lung adenocarcinoma. J. Oncol., 2015, 2015, 1-8. doi: 10.1155/2015/316745 PMID: 25733977Li, Z.H.; Zhang, H.; Yang, Z.G.; Wen, G.Q.; Cui, Y.B.; Shao, G.G. Prognostic significance of serum microRNA-210 levels in nonsmall-cell lung cancer. J. Int. Med. Res., 2013, 41(5), 1437-1444. doi: 10.1177/0300060513497560 PMID: 24065453Ono, S.; Lam, S.; Nagahara, M.; Hoon, D. Circulating microRNA biomarkers as liquid biopsy for cancer patients: Pros and cons of current assays. J. Clin. Med., 2015, 4(10), 1890-1907. doi: 10.3390/jcm4101890 PMID: 26512704Bao, Y.; Deng, L.; Su, D.; Xiao, J.; Ge, D.; Geng, Y.; Jing, H. Identification of crucial microRNAs and genes in hypoxia-induced human lung adenocarcinoma cells. Onco. Targets Ther., 2016, 9, 4605-4616. doi: 10.2147/OTT.S103430 PMID: 27524914Vaupel, P.; Flood, A.B.; Swartz, H.M. Oxygenation status of malignant tumors vs. Normal tissues: Critical evaluation and updated data source based on direct measurements with po2 microsensors. Appl. Magn. Reson., 2021, 52(10), 1451-1479. doi: 10.1007/s00723-021-01383-6Höckel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst., 2001, 93(4), 266-276. doi: 10.1093/jnci/93.4.266 PMID: 11181773D’Alonzo, R.A.; Gill, S.; Rowshanfarzad, P.; Keam, S.; MacKinnon, K.M.; Cook, A.M.; Ebert, M.A. In vivo noninvasive preclinical tumor hypoxia imaging methods: A review. Int. J. Radiat. Biol., 2021, 97(5), 593-631. doi: 10.1080/09553002.2021.1900943 PMID: 33703994Vaupel, P.; Schlenger, K.; Knoop, C.; Höckel, M. Oxygenation of human tumors: Evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res., 1991, 51(12), 3316-3322. PMID: 2040005Su, Q.; Wang, J.; Fan, M.; Ghauri, M.A.; Ullah, A.; Wang, B.; Dai, B.; Zhan, Y.; Zhang, D.; Zhang, Y. Sanguinarine disrupts the colocalization and interaction of HIF-1α with tyrosine and serine phosphorylated-STAT3 in breast cancer. J. Cell. Mol. Med., 2020, 24(6), 3756-3761. doi: 10.1111/jcmm.15056 PMID: 32065498Ziółkowska-Suchanek, I. Mimicking tumor hypoxia in non-small cell lung cancer employing three-dimensional in vitro models. Cells, 2021, 10(1), 141. doi: 10.3390/cells10010141 PMID: 33445709Vaupel, P.; Höckel, M.; Mayer, A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal., 2007, 9(8), 1221-1236. doi: 10.1089/ars.2007.1628 PMID: 17536958Emami Nejad, A.; Najafgholian, S.; Rostami, A.; Sistani, A.; Shojaeifar, S.; Esparvarinha, M.; Nedaeinia, R.; Haghjooy Javanmard, S.; Taherian, M.; Ahmadlou, M.; Salehi, R.; Sadeghi, B.; Manian, M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell Int., 2021, 21(1), 62. doi: 10.1186/s12935-020-01719-5 PMID: 33472628De Mello, R.A.; Luis, M.; Araújo, A.; Reis, R.M.; Hespanhol, V. The role of angiogenesis in non-small cell lung cancer tumor behavior. In: Biochemical Basis and Therapeutic Implications of Angiogenesis; Mehta, J.L.; Mathur, P.; Dhalla, N.S., Eds.; Springer International Publishing: Cham, 2017; pp. 217-239. doi: 10.1007/978-3-319-61115-0_10Powers, K.A.; Dhamoon, A.S. Physiology, pulmonary ventilation and perfusion. In: StatPearls; StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.,: Treasure Island (FL), 2022.Jiang, G.M.; Zhao, J.W.; Chen, Y.X.; Tian, F. Blood supply of pulmonary metastases and its clinical significance. Chin. J. Cancer, 2006, 25(7), 885-887. PMID: 16831283Jamil, A.; Kasi, A. Lung Metastasis. In: StatPearls; StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC: Treasure Island (FL), 2022.Bobba, R.K.; Holly, J.S.; Loy, T.; Perry, M.C. Scar carcinoma of the lung: A historical perspective. Clin. Lung Cancer, 2011, 12(3), 148-154. doi: 10.1016/j.cllc.2011.03.011 PMID: 21663856Ortiz-Prado, E.; Dunn, J.F.; Vasconez, J.; Castillo, D.; Viscor, G. Partial pressure of oxygen in the human body: A general review. Am. J. Blood Res., 2019, 9(1), 1-14. PMID: 30899601Semenza, G.L. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim. Biophys. Acta Mol. Cell Res., 2016, 1863(3), 382-391. doi: 10.1016/j.bbamcr.2015.05.036 PMID: 26079100Harris, A.L. Hypoxia-a key regulatory factor in tumour growth. Nat. Rev. Cancer, 2002, 2(1), 38-47. doi: 10.1038/nrc704 PMID: 11902584Ancel, J.; Perotin, J.M.; Dewolf, M.; Launois, C.; Mulette, P.; Nawrocki-Raby, B.; Dalstein, V.; Gilles, C.; Deslée, G.; Polette, M.; Dormoy, V. Hypoxia in lung cancer management: A translational approach. Cancers, 2021, 13(14), 3421. doi: 10.3390/cancers13143421 PMID: 34298636Satija, S.; Kaur, H.; Tambuwala, M.M.; Sharma, P.; Vyas, M.; Khurana, N.; Sharma, N.; Bakshi, H.A.; Charbe, N.B.; Zacconi, F.C.; Aljabali, A.A.; Nammi, S.; Dureja, H.; Singh, T.G.; Gupta, G.; Dhanjal, D.S.; Dua, K.; Chellappan, D.K.; Mehta, M. Hypoxia-inducible factor (HIF): Fuel for cancer progression. Curr. Mol. Pharmacol., 2021, 14(3), 321-332. doi: 10.2174/1874467214666210120154929 PMID: 33494692Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA, 1995, 92(12), 5510-5514. doi: 10.1073/pnas.92.12.5510 PMID: 7539918Baqlouq, L.; Zihlif, M.; Hammad, H.; Thaib, T.M.A. Determining the relative gene expression level of hypoxia related genes in different cancer cell lines. Curr. Mol. Pharmacol., 2020, 14(1), 52-59. doi: 10.2174/1874467213666200521081653 PMID: 32436837Mayer, A.; Höckel, M.; Wree, A.; Vaupel, P. Microregional expression of glucose transporter-1 and oxygenation status: Lack of correlation in locally advanced cervical cancers. Clin. Cancer Res., 2005, 11(7), 2768-2773. doi: 10.1158/1078-0432.CCR-04-2344 PMID: 15814659Su, Q.; Fan, M.; Wang, J.; Ullah, A.; Ghauri, M.A.; Dai, B.; Zhan, Y.; Zhang, D.; Zhang, Y. Sanguinarine inhibits epithelial–mesenchymal transition via targeting HIF-1α/TGF-β feed-forward loop in hepatocellular carcinoma. Cell Death Dis., 2019, 10(12), 939. doi: 10.1038/s41419-019-2173-1 PMID: 31819036Mayer, A.; Wree, A.; Höckel, M.; Leo, C.; Pilch, H.; Vaupel, P. Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res., 2004, 64(16), 5876-5881. doi: 10.1158/0008-5472.CAN-03-3566 PMID: 15313932Mayer, A.; Höckel, M.; Wree, A.; Leo, C.; Horn, L.C.; Vaupel, P. Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia. Cancer Res., 2008, 68(12), 4719-4726. doi: 10.1158/0008-5472.CAN-07-6339 PMID: 18559518Ren, W.; Mi, D.; Yang, K.; Cao, N.; Tian, J.; Li, Z.; Ma, B. The expression of hypoxia-inducible factor-1α and its clinical significance in lung cancer: A systematic review and meta-analysis. Swiss Med. Wkly., 2013, 143, w13855. doi: 10.4414/smw.2013.13855 PMID: 24018850Wilson, W.R.; Hay, M.P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer, 2011, 11(6), 393-410. doi: 10.1038/nrc3064 PMID: 21606941Wardman, P. Chemical radiosensitizers for use in radiotherapy. In: Clinical oncology (Royal College of Radiologists); (Great Britain), 2007; 19, pp. (6)497-417. doi: 10.1016/j.clon.2007.03.010Peters, L.; Rischin, D. Elusive goal of targeting tumor hypoxia for therapeutic gain. J. Clin. Oncol., 2012, 30(15), 1741-1743. doi: 10.1200/JCO.2011.40.8294 PMID: 22508811Li, L.; Hu, M.; Zhu, H.; Zhao, W.; Yang, G.; Yu, J. Comparison of 18F-Fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. Clin. Lung Cancer, 2010, 11(5), 335-340. doi: 10.3816/CLC.2010.n.042 PMID: 20837459Trinkaus, M.E.; Blum, R.; Rischin, D.; Callahan, J.; Bressel, M.; Segard, T.; Roselt, P.; Eu, P.; Binns, D.; MacManus, M.P.; Ball, D.; Hicks, R.J. Imaging of hypoxia with 18 F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J. Med. Imaging Radiat. Oncol., 2013, 57(4), 475-481. doi: 10.1111/1754-9485.12086 PMID: 23870348van Elmpt, W.; Zegers, C.M.L.; Reymen, B.; Even, A.J.G.; Dingemans, A.M.C.; Oellers, M.; Wildberger, J.E.; Mottaghy, F.M.; Das, M.; Troost, E.G.C.; Lambin, P. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43(2), 240-248. doi: 10.1007/s00259-015-3169-4 PMID: 26338178Tirpe, A.A.; Gulei, D.; Ciortea, S.M.; Crivii, C.; Berindan-Neagoe, I. Hypoxia: Overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. Int. J. Mol. Sci., 2019, 20(24), 6140. doi: 10.3390/ijms20246140 PMID: 31817513Duan, C. Hypoxia-inducible factor 3 biology: Complexities and emerging themes. Am. J. Physiol. Cell Physiol., 2016, 310(4), C260-C269. doi: 10.1152/ajpcell.00315.2015 PMID: 26561641Liao, C.; Zhang, Q. Understanding the oxygen-sensing pathway and its therapeutic implications in diseases. Am. J. Pathol., 2020, 190(8), 1584-1595. doi: 10.1016/j.ajpath.2020.04.003 PMID: 32339495Joshi, S.; Singh, A.R.; Durden, D.L. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J. Biol. Chem., 2014, 289(33), 22785-22797. doi: 10.1074/jbc.M114.587493 PMID: 24982421Pore, N.; Jiang, Z.; Shu, H.K.; Bernhard, E.; Kao, G.D.; Maity, A. Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol. Cancer Res., 2006, 4(7), 471-479. doi: 10.1158/1541-7786.MCR-05-0234 PMID: 16849522Cao, Y.; Eble, J.M.; Moon, E.; Yuan, H.; Weitzel, D.H.; Landon, C.D.; Yu-Chih Nien, C.; Hanna, G.; Rich, J.N.; Provenzale, J.M.; Dewhirst, M.W. Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res., 2013, 73(20), 6230-6242. doi: 10.1158/0008-5472.CAN-12-1345 PMID: 23959856Moniz, S.; Bandarra, D.; Biddlestone, J.; Campbell, K.J.; Komander, D.; Bremm, A.; Rocha, S. Cezanne regulates E2F1-dependent HIF2α expression. J. Cell Sci., 2015, 128(16), 3082-3093. PMID: 26148512Son, S.W.; Yun, B.D.; Song, M.G.; Lee, J.K.; Choi, S.Y.; Kuh, H.J.; Park, J.K. The hypoxia–long noncoding rna interaction in solid cancers. Int. J. Mol. Sci., 2021, 22(14), 7261. doi: 10.3390/ijms22147261 PMID: 34298879Poon, E.; Harris, A.L.; Ashcroft, M. Targeting the hypoxia-inducible factor (HIF) pathway in cancer. Expert Rev. Mol. Med., 2009, 11, e26. doi: 10.1017/S1462399409001173 PMID: 19709449Bertout, J.A.; Majmundar, A.J.; Gordan, J.D.; Lam, J.C.; Ditsworth, D.; Keith, B.; Brown, E.J.; Nathanson, K.L.; Simon, M.C. HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc. Natl. Acad. Sci. USA, 2009, 106(34), 14391-14396. doi: 10.1073/pnas.0907357106 PMID: 19706526Nardinocchi, L.; Puca, R.; D’Orazi, G. HIF-1α antagonizes p53- mediated apoptosis by triggering HIPK2 degradation. Aging (Albany NY), 2011, 3(1), 33-43. doi: 10.18632/aging.100254 PMID: 21248371Wang, X.; Dong, J.; Jia, L.; Zhao, T.; Lang, M.; Li, Z.; Lan, C.; Li, X.; Hao, J.; Wang, H.; Qin, T.; Huang, C.; Yang, S.; Yu, M.; Ren, H. HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma. Cancer Lett., 2017, 393, 113-124. doi: 10.1016/j.canlet.2017.01.032 PMID: 28153790Zhang, L.; Huang, G.; Li, X.; Zhang, Y.; Jiang, Y.; Shen, J.; Liu, J.; Wang, Q.; Zhu, J.; Feng, X.; Dong, J.; Qian, C. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma. BMC Cancer, 2013, 13(1), 108. doi: 10.1186/1471-2407-13-108 PMID: 23496980Choueiri, T.K.; Kaelin, W.G., Jr Targeting the HIF2–VEGF axis in renal cell carcinoma. Nat. Med., 2020, 26(10), 1519-1530. doi: 10.1038/s41591-020-1093-z PMID: 33020645Ravi, R.; Mookerjee, B.; Bhujwalla, Z.M.; Sutter, C.H.; Artemov, D.; Zeng, Q.; Dillehay, L.E.; Madan, A.; Semenza, G.L.; Bedi, A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev., 2000, 14(1), 34-44. doi: 10.1101/gad.14.1.34 PMID: 10640274Meijer, T.W.H.; Kaanders, J.H.A.M.; Span, P.N.; Bussink, J. Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin. Cancer Res., 2012, 18(20), 5585-5594. doi: 10.1158/1078-0432.CCR-12-0858 PMID: 23071360Samanta, D.; Gilkes, D.M.; Chaturvedi, P.; Xiang, L.; Semenza, G.L. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc. Natl. Acad. Sci. USA, 2014, 111(50), E5429-E5438. doi: 10.1073/pnas.1421438111 PMID: 25453096Noman, M.Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med., 2014, 211(5), 781-790. doi: 10.1084/jem.20131916 PMID: 24778419Imtiyaz, H.Z.; Williams, E.P.; Hickey, M.M.; Patel, S.A.; Durham, A.C.; Yuan, L.J.; Hammond, R.; Gimotty, P.A.; Keith, B.; Simon, M.C. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest., 2010, 120(8), 2699-2714. doi: 10.1172/JCI39506 PMID: 20644254Talks, K.L.; Turley, H.; Gatter, K.C.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J.; Harris, A.L. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol., 2000, 157(2), 411-421. doi: 10.1016/S0002-9440(10)64554-3 PMID: 10934146Liu, Y.M.; Ying, S.P.; Huang, Y.R.; Pan, Y.; Chen, W.J.; Ni, L.Q.; Xu, J.Y.; Shen, Q.Y.; Liang, Y. Expression of HIF-1α and HIF-2α correlates to biological and clinical significance in papillary thyroid carcinoma. World J. Surg. Oncol., 2015, 14(1), 30. doi: 10.1186/s12957-016-0785-9 PMID: 26846782Zhang, L.; Chen, Q.; Hu, J.; Chen, Y.; Liu, C.; Xu, C. Expression of HIF-2α and VEGF in cervical squamous cell carcinoma and its clinical significance. BioMed Res. Int., 2016, 2016, 5631935. PMID: 27413748Moreno Roig, E.; Groot, A.; Yaromina, A.; Hendrickx, T.; Barbeau, L.; Giuranno, L.; Dams, G.; Ient, J.; Olivo Pimentel, V.; van Gisbergen, M.; Dubois, L.; Vooijs, M. HIF-1α and HIF-2α differently regulate the radiation sensitivity of NSCLC cells. Cells, 2019, 8(1), 45. doi: 10.3390/cells8010045 PMID: 30642030Isono, T.; Chano, T.; Yoshida, T.; Kageyama, S.; Kawauchi, A.; Suzaki, M.; Yuasa, T. Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas. Am. J. Cancer Res., 2016, 6(10), 2263-2276. PMID: 27822416Downes, NL; Laham-Karam, N; Kaikkonen, MU; Ylä-Herttuala, S. Differential but Complementary HIF1α and HIF2α transcriptional regulation. J. Am. Soc. Gene. Ther., 2018, 26(7), 1735-1745. doi: 10.1016/j.ymthe.2018.05.004Loboda, A.; Jozkowicz, A.; Dulak, J. HIF-1 and HIF-2 transcription factors — Similar but not identical. Mol. Cells, 2010, 29(5), 435-442. doi: 10.1007/s10059-010-0067-2 PMID: 20396958Hoefflin, R.; Harlander, S.; Schäfer, S.; Metzger, P.; Kuo, F.; Schönenberger, D.; Adlesic, M.; Peighambari, A.; Seidel, P.; Chen, C.; Consenza-Contreras, M.; Jud, A.; Lahrmann, B.; Grabe, N.; Heide, D.; Uhl, F.M.; Chan, T.A.; Duyster, J.; Zeiser, R.; Schell, C.; Heikenwalder, M.; Schilling, O.; Hakimi, A.A.; Boerries, M.; Frew, I.J. HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nat. Commun., 2020, 11(1), 4111. doi: 10.1038/s41467-020-17873-3 PMID: 32807776Bertout, J.A.; Patel, S.A.; Simon, M.C. The impact of O2 availability on human cancer. Nat. Rev. Cancer, 2008, 8(12), 967-975. doi: 10.1038/nrc2540 PMID: 18987634Brustugun, O.T. Hypoxia as a cause of treatment failure in non-small cell carcinoma of the lung. Semin. Radiat. Oncol., 2015, 25(2), 87-92. doi: 10.1016/j.semradonc.2014.11.006 PMID: 25771412Dewhirst, M.W.; Birer, S.R. Oxygen-enhanced MRI is a major advance in tumor hypoxia imaging. Cancer Res., 2016, 76(4), 769-772. doi: 10.1158/0008-5472.CAN-15-2818 PMID: 26837768Sharma, R.A.; Plummer, R.; Stock, J.K.; Greenhalgh, T.A.; Ataman, O.; Kelly, S.; Clay, R.; Adams, R.A.; Baird, R.D.; Billingham, L.; Brown, S.R.; Buckland, S.; Bulbeck, H.; Chalmers, A.J.; Clack, G.; Cranston, A.N.; Damstrup, L.; Ferraldeschi, R.; Forster, M.D.; Golec, J.; Hagan, R.M.; Hall, E.; Hanauske, A.R.; Harrington, K.J.; Haswell, T.; Hawkins, M.A.; Illidge, T.; Jones, H.; Kennedy, A.S.; McDonald, F.; Melcher, T.; O’Connor, J.P.B.; Pollard, J.R.; Saunders, M.P.; Sebag-Montefiore, D.; Smitt, M.; Staffurth, J.; Stratford, I.J.; Wedge, S.R. Clinical development of new drug–radiotherapy combinations. Nat. Rev. Clin. Oncol., 2016, 13(10), 627-642. doi: 10.1038/nrclinonc.2016.79 PMID: 27245279Salem, A.; Asselin, M.C.; Reymen, B.; Jackson, A.; Lambin, P.; West, C.M.L.; O’Connor, J.P.B.; Faivre-Finn, C. Targeting hypoxia to improve non–small cell lung cancer outcome. J. Natl. Cancer Inst., 2018, 110(1), 14-30. doi: 10.1093/jnci/djx160 PMID: 28922791Son, S.W.; Lee, H.Y.; Moeng, S.; Kuh, H.J.; Choi, S.Y.; Park, J.K. Participation of MicroRNAs in the treatment of cancer with phytochemicals. Molecules, 2020, 25(20), 4701. doi: 10.3390/molecules25204701 PMID: 33066509Montané, X.; Kowalczyk, O.; Reig-Vano, B.; Bajek, A.; Roszkowski, K.; Tomczyk, R.; Pawliszak, W.; Giamberini, M.; Mocek-Płóciniak, A.; Tylkowski, B. Current perspectives of the applications of polyphenols and flavonoids in cancer therapy. Molecules, 2020, 25(15), 3342. doi: 10.3390/molecules25153342 PMID: 32717865Mitra, T.; Bhattacharya, R. Phytochemicals modulate cancer aggressiveness: A review depicting the anticancer efficacy of dietary polyphenols and their combinations. J. Cell. Physiol., 2020, 235(11), 7696-7708. doi: 10.1002/jcp.29703 PMID: 32324275Wheelock, C.E.; Goss, V.M.; Balgoma, D.; Nicholas, B.; Brandsma, J.; Skipp, P.J.; Snowden, S.; Burg, D.; D’Amico, A.; Horvath, I.; Chaiboonchoe, A.; Ahmed, H.; Ballereau, S.; Rossios, C.; Chung, K.F.; Montuschi, P.; Fowler, S.J.; Adcock, I.M.; Postle, A.D.; Dahlén, S.E.; Rowe, A.; Sterk, P.J.; Auffray, C.; Djukanović, R. Application of ’omics technologies to biomarker discovery in inflammatory lung diseases. Eur. Respir. J., 2013, 42(3), 802-825. doi: 10.1183/09031936.00078812 PMID: 23397306Rong, Z.H.U.; Lingyun, D.A.I.; Jinxing, L.I.U.; Ying, G.U.O. Diagnostic classification of lung cancer using deep transfer learning technology and multi-omics data. Chin. J. Electron., 2021, 30(5), 843-852. doi: 10.1049/cje.2021.06.006Altorki, N.K.; Markowitz, G.J.; Gao, D.; Port, J.L.; Saxena, A.; Stiles, B.; McGraw, T.; Mittal, V. The lung microenvironment: An important regulator of tumour growth and metastasis. Nat. Rev. Cancer, 2019, 19(1), 9-31. doi: 10.1038/s41568-018-0081-9 PMID: 30532012Schito, L.; Semenza, G.L. Hypoxia-inducible factors: Master regulators of cancer progression. Trends Cancer, 2016, 2(12), 758-770. doi: 10.1016/j.trecan.2016.10.016 PMID: 28741521Iommarini, L.; Porcelli, A.M.; Gasparre, G.; Kurelac, I. Non-canonical mechanisms regulating hypoxia-inducible factor 1 alpha in cancer. Front. Oncol., 2017, 7, 286. doi: 10.3389/fonc.2017.00286 PMID: 29230384LaGory, E.L.; Giaccia, A.J. The ever-expanding role of HIF in tumour and stromal biology. Nat. Cell Biol., 2016, 18(4), 356-365. doi: 10.1038/ncb3330 PMID: 27027486Walsh, J.C.; Lebedev, A.; Aten, E.; Madsen, K.; Marciano, L.; Kolb, H.C. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid. Redox Signal., 2014, 21(10), 1516-1554. doi: 10.1089/ars.2013.5378 PMID: 24512032Robinson, M.F.; Dupuis, N.P.; Kusumoto, T.; Liu, F.; Menon, K.; Teicher, B.A. Increased tumor oxygenation and radiation sensitivity in two rat tumors by a hemoglobin-based, oxygen-carrying preparation. Artif. Cells Blood Substit. Immobil. Biotechnol., 1995, 23(3), 431-438. doi: 10.3109/10731199509117959 PMID: 7493064Sun, C.J.; Li, C.; Lv, H.B.; Zhao, C.; Yu, J.M.; Wang, G.H.; Luo, Y.X.; Li, Y.; Xiao, M.; Yin, J.; Lang, J.Y. Comparing CT perfusion with oxygen partial pressure in a rabbit VX2 soft-tissue tumor model. J. Radiat. Res. (Tokyo), 2014, 55(1), 183-190. doi: 10.1093/jrr/rrt092 PMID: 24078878Doss, M.; Zhang, J.J.; Bélanger, M.J.; Stubbs, J.B.; Hostetler, E.D.; Alpaugh, K.; Kolb, H.C.; Yu, J.Q. Biodistribution and radiation dosimetry of the hypoxia marker 18F–HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl. Med. Commun., 2010, 31(12), 1016-1024. doi: 10.1097/MNM.0b013e3283407950 PMID: 20948452Logothetis, N.K. The underpinnings of the BOLD functional magnetic resonance imaging signal. J. Neurosci., 2003, 23(10), 3963-3971. doi: 10.1523/JNEUROSCI.23-10-03963.2003 PMID: 12764080Daponte, A.; Ioannou, M.; Mylonis, I.; Simos, G.; Minas, M.; Messinis, I.E.; Koukoulis, G. Prognostic significance of Hypoxia-Inducible Factor 1 alpha(HIF-1alpha) expression in serous ovarian cancer: An immunohistochemical study. BMC Cancer, 2008, 8(1), 335. doi: 10.1186/1471-2407-8-335 PMID: 19014607Nordsmark, M.; Loncaster, J.; Aquino-Parsons, C.; Chou, S.C.; Gebski, V.; West, C.; Lindegaard, J.C.; Havsteen, H.; Davidson, S.E.; Hunter, R.; Raleigh, J.A.; Overgaard, J. The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: A prospective international multi-center study. Radiother. Oncol., 2006, 80(2), 123-131. doi: 10.1016/j.radonc.2006.07.010 PMID: 16890316Dunwoodie, S.L. The role of hypoxia in development of the Mammalian embryo. Dev. Cell, 2009, 17(6), 755-773. doi: 10.1016/j.devcel.2009.11.008 PMID: 20059947DiGiacomo, J.W.; Gilkes, D.M. Tumor hypoxia as an enhancer of inflammation-mediated metastasis: Emerging therapeutic strategies. Target. Oncol., 2018, 13(2), 157-173. doi: 10.1007/s11523-018-0555-4 PMID: 29423593DiGiacomo, J.W.; Gilkes, D.M. Therapeutic strategies to block the hypoxic response. Adv. Exp. Med. Biol., 2019, 1136, 141-157. doi: 10.1007/978-3-030-12734-3_10 PMID: 31201722