Abstract
Radiotherapy (RT) is considered as a standard in the treatment of most solid cancers, including glioblastoma, lung, breast, rectal, prostate, colorectal, cervical, esophageal, and head and neck cancers. The main challenge in RT is tumor cell radioresistance associated with a high risk of locoregional relapse and distant metastasis. Despite significant progress in understanding mechanisms of radioresistance, its prediction and overcoming remain unresolved. This review presents the state-of-the-art for the potential universal biomarkers correlated to the radioresistance and poor outcome in different cancers. We describe radioresistance biomarkers functionally attributed to DNA repair, signal transduction, hypoxia, and angiogenesis. We also focus on high throughput genetic and proteomic studies, which revealed a set of molecular biomarkers related to radioresistance. In conclusion, we discuss biomarkers which are overlapped in most several cancers.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ai D, Dou Y, Nan Z et al (2021) CD68(+) macrophage infiltration associates with poor outcome of hpv negative oral squamous carcinoma patients receiving radiation: poly(I:C) enhances radiosensitivity of CAL-27 cells but promotes macrophage recruitment through HMGB1. Front Oncol 11:740622. https://doi.org/10.3389/fonc.2021.740622
Akervall J, Nandalur S, Zhang J et al (2014) A novel panel of biomarkers predicts radioresistance in patients with squamous cell carcinoma of the head and neck. Eur J Cancer 50:570–581. https://doi.org/10.1016/j.ejca.2013.11.007
Aleksic T, Verrill C, Bryant RJ et al (2017) IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer. Br J Cancer 117:1600–1606. https://doi.org/10.1038/bjc.2017.337
Alsubhi N, Middleton F, Abdel-Fatah TMA et al (2016) Chk1 phosphorylated at serine345 is a predictor of early local recurrence and radio-resistance in breast cancer. Mol Oncol 10:213–223. https://doi.org/10.1016/j.molonc.2015.09.009
Ansems M, Span PN (2020) The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts. Clin Transl Radiat Oncol 22:90–97. https://doi.org/10.1016/j.ctro.2020.04.001
Aponte PM, Caicedo A (2017) Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. https://doi.org/10.1155/2017/5619472
Arechaga-Ocampo E, Lopez-Camarillo C, Villegas-Sepulveda N et al (2017) Tumor suppressor miR-29c regulates radioresistance in lung cancer cells. Tumour Biol J Int Soc Oncodev Biol Med 39:1010428317695010. https://doi.org/10.1177/1010428317695010
Azevedo Martins JM, Rabelo-Santos SH, do Amaral Westin MC, Zeferino LC, (2020) Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis. BMC Cancer 20:660. https://doi.org/10.1186/s12885-020-07150-3
Baek J-H, Yun HS, Kwon GT et al (2019) PLOD3 suppression exerts an anti-tumor effect on human lung cancer cells by modulating the PKC-delta signaling pathway. Cell Death Dis 10:156. https://doi.org/10.1038/s41419-019-1405-8
Balermpas P, Rödel F, Liberz R et al (2014) Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences. Br J Cancer 111:1509–1518. https://doi.org/10.1038/bjc.2014.446
Balkwill F, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596. https://doi.org/10.1242/JCS.116392
Bargiela-Iparraguirre J, Prado-Marchal L, Fernandez-Fuente M et al (2016) CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response. Sci Rep 6:21519. https://doi.org/10.1038/srep21519
Barker HE, Paget JTE, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425. https://doi.org/10.1038/nrc3958
Baskar R, Itahana K (2017) Radiation therapy and cancer control in developing countries: can we save more lives? Int J Med Sci 14:13–17. https://doi.org/10.7150/ijms.17288
Bayo J, Tran TA, Wang L et al (2018) Jumonji inhibitors overcome radioresistance in cancer through changes in H3K4 methylation at double-strand breaks. Cell Rep 25:1040-1050.e5. https://doi.org/10.1016/j.celrep.2018.09.081
Berbecka M, Forma A, Baj J et al (2021) A systematic review of the cyclooxygenase-2 (COX-2) expression in rectal cancer patients treated with preoperative radiotherapy or radiochemotherapy. J Clin Med. https://doi.org/10.3390/jcm10194443
Berlin A, Lalonde E, Sykes J et al (2014) NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer. Oncotarget 5:11081–11090. https://doi.org/10.18632/oncotarget.2404
Bhattacharya P, Shetake NG, Pandey BN, Kumar A (2018) Receptor tyrosine kinase signaling in cancer radiotherapy and its targeting for tumor radiosensitization. Int J Radiat Biol 94:628–644. https://doi.org/10.1080/09553002.2018.1478160
Boulle G, Velut Y, Mansuet-Lupo A et al (2020) Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+ double positive T cell density in locally advanced N2 non-small-cell lung carcinoma. Eur J Cancer 135:221–229. https://doi.org/10.1016/j.ejca.2020.04.040
Cabrera-Licona A, Pérez-Añorve IX, Flores-Fortis M et al (2021) Deciphering the epigenetic network in cancer radioresistance. Radiother Oncol J Eur Soc Ther Radiol Oncol 159:48–59. https://doi.org/10.1016/j.radonc.2021.03.012
Cantini L, Calzone L, Martignetti L et al (2017) Classification of gene signatures for their information value and functional redundancy. Npj Syst Biol Appl 4:2. https://doi.org/10.1038/s41540-017-0038-8
Chang H, Wei J-W, Tao Y-L et al (2018) CCR6 is a predicting biomarker of radiosensitivity and potential target of radiosensitization in rectal cancer. Cancer Res Treat 50:1203–1213. https://doi.org/10.4143/crt.2017.538
Chen HHW, Su W-C, Chou C-Y et al (2005) Increased expression of nitric oxide synthase and cyclooxygenase-2 is associated with poor survival in cervical cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 63:1093–1100. https://doi.org/10.1016/j.ijrobp.2005.03.062
Chen M-F, Chen P-T, Lu MS et al (2013) IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer 12:26. https://doi.org/10.1186/1476-4598-12-26
Chen Y, Li X, Wu S et al (2014) Expression of HIF-1α and CAIX in nasopharyngeal carcinoma and their correlation with patients’ prognosis. Med Oncol 31:304. https://doi.org/10.1007/s12032-014-0304-1
Chen X, Xu Y, Liao X et al (2016) Plasma miRNAs in predicting radiosensitivity in non-small cell lung cancer. Tumour Biol 37:11927–11936. https://doi.org/10.1007/s13277-016-5052-8
Chen X, Wu L, Li D et al (2018) Radiosensitizing effects of miR-18a-5p on lung cancer stem-like cells via downregulating both ATM and HIF-1α. Cancer Med 7:3834–3847. https://doi.org/10.1002/cam4.1527
Chiu T-J, Lu H-I, Chen C-H et al (2018) Osteopontin expression is associated with the poor prognosis in patients with locally advanced esophageal squamous cell carcinoma receiving preoperative chemoradiotherapy. Biomed Res Int 2018:9098215. https://doi.org/10.1155/2018/9098215
Choi CH, Chung J-Y, Kang JH et al (2020a) Chemoradiotherapy response prediction model by proteomic expressional profiling in patients with locally advanced cervical cancer. Gynecol Oncol 157:437–443. https://doi.org/10.1016/j.ygyno.2020.02.017
Choi J, Yoon YN, Kim N et al (2020b) Predicting radiation resistance in breast cancer with expression status of phosphorylated S6K1. Sci Rep 10:641. https://doi.org/10.1038/s41598-020-57496-8
Chow K-C, Chiou S-H, Ho S-P et al (2003) The elevated serum interleukin-6 correlates with the increased serum butyrate level in patients with nasopharyngeal carcinoma. Oncol Rep 10:813–819
Chung YM, Kim B-G, Park C-S et al (2005) Increased expression of ICAM-3 is associated with radiation resistance in cervical cancer. Int J Cancer 117:194–201. https://doi.org/10.1002/ijc.21180
Couch DG, Hemingway DM (2016) Complete radiotherapy response in rectal cancer: a review of the evidence. World J Gastroenterol 22:467–470. https://doi.org/10.3748/wjg.v22.i2.467
Das M, Abdelmaksoud MHK, Loo BWJ, Kothary N (2010) Alternatives to surgery for early stage non-small cell lung cancer-ready for prime time? Curr Treat Options Oncol 11:24–35. https://doi.org/10.1007/s11864-010-0119-z
Davies JM, Trembath D, Deal AM et al (2011) Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy. Radiat Oncol 6:114. https://doi.org/10.1186/1748-717X-6-114
de Jong MC, Ten Hoeve JJ, Grénman R et al (2015) Pretreatment microRNA expression impacting on epithelial-to-mesenchymal transition predicts intrinsic radiosensitivity in head and neck cancer cell lines and patients. Clin Cancer Res 21:5630–5638. https://doi.org/10.1158/1078-0432.CCR-15-0454
Dehing-Oberije C, Aerts H, Yu S et al (2011) Development and validation of a prognostic model using blood biomarker information for prediction of survival of non-small-cell lung cancer patients treated with combined chemotherapy and radiation or radiotherapy alone (NCT00181519, NCT00573040, and NCT. Int J Radiat Oncol Biol Phys 81:360–368. https://doi.org/10.1016/j.ijrobp.2010.06.011
Drobin K, Marczyk M, Halle M et al (2020) Molecular profiling for predictors of radiosensitivity in patients with breast or head-and-neck cancer. Cancers (basel). https://doi.org/10.3390/cancers12030753
DuBois S, Demetri G (2007) Markers of angiogenesis and clinical features in patients with sarcoma. Cancer 109:813–819. https://doi.org/10.1002/cncr.22455
Etiz D, Ataizi FC, Bayman E et al (2013) Prognostic value of osteopontin in patients treated with primary radiotherapy for head and neck cancer. Asian Pac J Cancer Prev 14:5175–5178. https://doi.org/10.7314/apjcp.2013.14.9.5175
Fardi M, Solali S, Farshdousti Hagh M (2018) Epigenetic mechanisms as a new approach in cancer treatment: an updated review. Genes Dis 5:304–311. https://doi.org/10.1016/j.gendis.2018.06.003
Farhood B, Najafi M, Mortezaee K (2019) CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 234:8509–8521. https://doi.org/10.1002/jcp.27782
Ferrandon S, DeVecchio J, Duraes L et al (2020) CoA synthase (COASY) mediates radiation resistance via pi3k signaling in rectal cancer. Cancer Res 80:334–346. https://doi.org/10.1158/0008-5472.CAN-19-1161
Fiedler M, Weber F, Hautmann MG et al (2018) Biological predictors of radiosensitivity in head and neck squamous cell carcinoma. Clin Oral Investig 22:189–200. https://doi.org/10.1007/s00784-017-2099-x
Freudlsperger C, Horn D, Weißfuß S et al (2015) Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma. Int J Cancer 136:2775–2785. https://doi.org/10.1002/ijc.29328
Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14:717–734. https://doi.org/10.1038/nrclinonc.2017.101
Fu Z-Z, Sun X-D, Li P et al (2014) Relationship between serum VEGF level and radiosensitivity of patients with nonsmall cell lung cancer among asians: a meta-analysis. DNA Cell Biol 33:426–437. https://doi.org/10.1089/dna.2013.2249
Fu H-C, Chuang I-C, Yang Y-C et al (2018) Low P16(INK4A) expression associated with high expression of cancer stem cell markers predicts poor prognosis in cervical cancer after radiotherapy. Int J Mol Sci. https://doi.org/10.3390/ijms19092541
Garg AK, Jhingran A, Klopp AH et al (2010) Expression of nuclear transcription factor kappa B in locally advanced human cervical cancer treated with definitive chemoradiation. Int J Radiat Oncol Biol Phys 78:1331–1336. https://doi.org/10.1016/j.ijrobp.2009.09.044
Genard G, Lucas S, Michiels C (2017) Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies. Front Immunol 8:828. https://doi.org/10.3389/fimmu.2017.00828
Goedegebuure RSA, de Klerk LK, Bass AJ et al (2019) Combining radiotherapy with anti-angiogenic therapy and immunotherapy; a therapeutic triad for cancer? Front Immunol 9:3107. https://doi.org/10.3389/fimmu.2018.03107
Gönen M (2009) Statistical aspects of gene signatures and molecular targets. Gastrointest Cancer Res 3:S19–S21
Göttgens E-L, van den Heuvel CN, de Jong MC et al (2019) ACLY (ATP Citrate Lyase) mediates radioresistance in head and neck squamous cell carcinomas and is a novel predictive radiotherapy biomarker. Cancers (basel). https://doi.org/10.3390/cancers11121971
Grün A, Kuhnt T, Schlomm T et al (2020) Repeat radiation for local recurrence of head and neck tumors and in prostate cancer. Dtsch Arztebl Int 117:167–174. https://doi.org/10.3238/arztebl.2020.0167
Ham I-H, Lee D, Hur H (2021) Cancer-associated fibroblast-induced resistance to chemotherapy and radiotherapy in gastrointestinal cancers. Cancers (basel) 13:1172. https://doi.org/10.3390/cancers13051172
Harrington KJ, Billingham LJ, Brunner TB et al (2011) Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers. Br J Cancer 105:628–639. https://doi.org/10.1038/bjc.2011.240
Hou H, Er P, Cheng J et al (2017) High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer. Cancer Med 6:1871–1881. https://doi.org/10.1002/cam4.1112
Huang R-X, Zhou P-K (2020) DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 5:60. https://doi.org/10.1038/s41392-020-0150-x
Huang K-H, Huang S-F, Chen I-H et al (2009) Methylation of RASSF1A, RASSF2A, and HIN-1 is associated with poor outcome after radiotherapy, but not surgery, in oral squamous cell carcinoma. Clin Cancer Res 15:4174–4180. https://doi.org/10.1158/1078-0432.CCR-08-2929
Huang X, Qian Y, Wu H et al (2015) Aberrant expression of osteopontin and E-cadherin indicates radiation resistance and poor prognosis for patients with cervical carcinoma. J Histochem Cytochem 63:88–98. https://doi.org/10.1369/0022155414561329
Huang L, Chen S, Yang WT, Shao Z (2017) Risk factors of locoregional relapse in locally advanced breast cancer treated with neoadjuvant chemotherapy following mastectomy and radiotherapy. Oncotarget 8:39703–39710. https://doi.org/10.18632/oncotarget.14407
Huang W, Shi G, Yong Z et al (2020) Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p. Cell Death Dis 11:504. https://doi.org/10.1038/s41419-020-2695-6
Hui EP, Chan ATC, Pezzella F et al (2002) Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 8:2595–2604
Hui EP, Sung FL, Yu BKH et al (2008) Plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. Clin Cancer Res 14:7080–7087. https://doi.org/10.1158/1078-0432.CCR-08-0364
Iwai Y, Ishida M, Tanaka Y et al (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99:12293–12297. https://doi.org/10.1073/pnas.192461099
Jing X, Yang F, Shao C et al (2019) Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer 18:157. https://doi.org/10.1186/s12943-019-1089-9
Johnson N, Shapiro GI (2010) Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor–chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets 14:1199. https://doi.org/10.1517/14728222.2010.525221
Kawanaka T, Kubo A, Ikushima H et al (2008) Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J Med Invest 55:78–86. https://doi.org/10.2152/jmi.55.78
Keir ME, Liang SC, Guleria I et al (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203:883–895. https://doi.org/10.1084/jem.20051776
Kim YB, Kim GE, Cho NH et al (2002) Overexpression of cyclooxygenase-2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy. Cancer 95:531–539. https://doi.org/10.1002/cncr.10684
Kim T-J, Lee J-W, Song SY et al (2006) Increased expression of pAKT is associated with radiation resistance in cervical cancer. Br J Cancer 94:1678–1682. https://doi.org/10.1038/sj.bjc.6603180
Kim BW, Cho H, Chung J-Y et al (2013) Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry. J Transl Med 11:185. https://doi.org/10.1186/1479-5876-11-185
Komdeur FL, Prins TM, van de Wall S et al (2017) CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. Oncoimmunology 6:e1338230. https://doi.org/10.1080/2162402X.2017.1338230
Kong M, Sung J-Y, Lee SH (2019) Reactive oxygen species modulator 1 as an adverse prognostic marker in stage III non-small cell lung cancer treated with radiotherapy: a retrospective pilot study. Onco Targets Ther 12:8263–8273. https://doi.org/10.2147/OTT.S217514
Köster F, Sauer L, Hoellen F et al (2020) PSMD9 expression correlates with recurrence after radiotherapy in patients with cervical cancer. Oncol Lett 20:581–588. https://doi.org/10.3892/ol.2020.11622
Koyama FC, Lopes Ramos CM, Ledesma F et al (2018) Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer. Br J Surg 105:e192–e203. https://doi.org/10.1002/bjs.10695
Kurokawa T, Nakagawa T, Matsusaka K et al (2020) Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer. Cancer Sci 111:1407–1416. https://doi.org/10.1111/cas.14338
Larionova I, Cherdyntseva N, Liu T et al (2019) Interaction of tumor-associated macrophages and cancer chemotherapy. Oncoimmunology 8:1596004. https://doi.org/10.1080/2162402X.2019.1596004
Larionova I, Tuguzbaeva G, Ponomaryova A et al (2020) Tumor-associated macrophages in human breast, colorectal, lung Ovarian and Prostate Cancers. Front Oncol 10:566511. https://doi.org/10.3389/fonc.2020.56651
Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J (2021) New angiogenic regulators produced by TAMs: perspective for targeting tumor angiogenesis. Cancers (basel). https://doi.org/10.3390/cancers13133253
Li K, Zhu X, Li L et al (2020) Identification of non-invasive biomarkers for predicting the radiosensitivity of nasopharyngeal carcinoma from serum microRNAs. Sci Rep 10:5161. https://doi.org/10.1038/s41598-020-61958-4
Liao L, Yan W-J, Tian C-M et al (2018) Knockdown of annexin A1 enhances radioresistance and inhibits apoptosis in nasopharyngeal carcinoma. Technol Cancer Res Treat 17:1533034617750309. https://doi.org/10.1177/1533034617750309
Lin H, Chen Z-T, Zhu X-D et al (2017) Serum CD166: A novel biomarker for predicting nasopharyngeal carcinoma response to radiotherapy. Oncotarget 8:62858–62867. https://doi.org/10.18632/oncotarget.16399
Lindegaard AM, von Buchwald C, Rasmussen JH et al (2020) Outcome in patients with isolated regional recurrence after primary radiotherapy for head and neck cancer. Head Neck 42:3161–3170. https://doi.org/10.1002/hed.26361
Lippens L, Van Bockstal M, De Jaeghere EA et al (2020) Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment. Int J Cancer 147:554–564. https://doi.org/10.1002/ijc.32893
Liu H-X, Li N, Wei L et al (2017a) High expression of Kruppel-like factor 4 as a predictor of poor prognosis for cervical cancer patient response to radiotherapy. Tumour Biol J Int Soc Oncodevelopmental Biol Med 39:1010428317710225. https://doi.org/10.1177/1010428317710225
Liu T, Zhang L, Joo D, Sun S-C (2017b) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23
Liu J-K, Liu H-F, Ding Y, Gao G-D (2018) Predictive value of microRNA let-7a expression for efficacy and prognosis of radiotherapy in patients with lung cancer brain metastasis: A case-control study. Medicine (baltimore) 97:e12847. https://doi.org/10.1097/MD.0000000000012847
Liu C, Hu Q, Hu K et al (2019) Increased CD8+CD28+ T cells independently predict better early response to stereotactic ablative radiotherapy in patients with lung metastases from non-small cell lung cancer. J Transl Med 17:120. https://doi.org/10.1186/s12967-019-1872-9
Liu G, Zeng X, Wu B et al (2020a) RNA-Seq analysis of peripheral blood mononuclear cells reveals unique transcriptional signatures associated with radiotherapy response of nasopharyngeal carcinoma and prognosis of head and neck cancer. Cancer Biol Ther 21:139–146. https://doi.org/10.1080/15384047.2019.1670521
Liu J, Bi K, Yang R et al (2020b) Role of DNA damage and repair in radiation cancer therapy: a current update and a look to the future. Int J Radiat Biol 96:1329–1338. https://doi.org/10.1080/09553002.2020.1807641
Liu Q, Liu S, Wang D (2020c) Overexpression of microRNA-21 decreased the sensitivity of advanced cervical cancer to chemoradiotherapy through SMAD7. Anticancer Drugs 31:272–281. https://doi.org/10.1097/CAD.0000000000000871
Loncaster JA, Cooper RA, Logue JP et al (2000) (2000) Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer 835(83):620–625. https://doi.org/10.1054/bjoc.2000.1319
Luo A, Zhou X, Shi X et al (2019) Exosome-derived miR-339-5p mediates radiosensitivity by targeting Cdc25A in locally advanced esophageal squamous cell carcinoma. Oncogene 38:4990–5006. https://doi.org/10.1038/s41388-019-0771-0
Lv J, An J, Zhang Y-D et al (2020) A three serum miRNA panel as diagnostic biomarkers of radiotherapy-related metastasis in non-small cell lung cancer. Oncol Lett 20:236. https://doi.org/10.3892/ol.2020.12099
Ma W, Yu J, Qin X, et al (2015) Radiation-induced microrna-622 causes radioresistance in colorectal cancer cells by down-regulating Rb. Oncotarget. 6:15984–15994. https://doi.org/10.18632/oncotarget.3762
Macedo-Silva C, Miranda-Gonçalves V, Lameirinhas A et al (2020) JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma. Cell Death Dis 11:1068. https://doi.org/10.1038/s41419-020-03279-y
Manders P, Sweep FCGJ, Tjan-Heijnen VCG et al (2003) Vascular endothelial growth factor independently predicts the efficacy of postoperative radiotherapy in node-negative breast cancer patients. Clin Cancer Res 9:6363–6370
Marampon F, Megiorni F, Camero S et al (2017) HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. Cancer Lett 397:1–11. https://doi.org/10.1016/j.canlet.2017.03.028
Moeller BJ, Yordy JS, Williams MD et al (2011) DNA repair biomarker profiling of head and neck cancer: Ku80 expression predicts locoregional failure and death following radiotherapy. Clin Cancer Res 17:2035–2043. https://doi.org/10.1158/1078-0432.CCR-10-2641
Moreno-Acosta P, Vallard A, Carrillo S et al (2017) Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma. Radiat Oncol 12:120. https://doi.org/10.1186/s13014-017-0856-2
Najafi M, Mortezaee K, Majidpoor J (2019) Cancer stem cell (CSC) resistance drivers. Life Sci 234:116781. https://doi.org/10.1016/j.lfs.2019.116781
Ning MS, Ahobila V, Jhingran A et al (2018) Outcomes and patterns of relapse after definitive radiation therapy for oligometastatic cervical cancer. Gynecol Oncol 148:132–138. https://doi.org/10.1016/j.ygyno.2017.10.017
Nowicka Z, Stawiski K, Tomasik B, Fendler W (2019) Extracellular miRNAs as biomarkers of head and neck cancer progression and metastasis. Int J Mol Sci 20:4799. https://doi.org/10.3390/ijms20194799
O’Cathail SM, Wu C-H, Thomas R et al (2021) NRF2 mediates therapeutic resistance to chemoradiation in colorectal cancer through a metabolic switch. Antioxidants 10:1380
Olivares-Urbano MA, Griñán-Lisón C, Marchal JA, Núñez MI (2020) CSC radioresistance: a therapeutic challenge to improve radiotherapy effectiveness in cancer. Cells 9:1651. https://doi.org/10.3390/cells9071651
Ostheimer C, Bache M, Güttler A et al (2014) A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer. Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor. Strahlenther Onkol 190:276–282. https://doi.org/10.1007/s00066-013-0484-1
Ostheimer C, Evers C, Bache M et al (2018) Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume. Strahlenther Onkol 194:539–551. https://doi.org/10.1007/s00066-017-1255-1
Otani K, Naito Y, Sakaguchi Y et al (2016) Cell-cycle-controlled radiation therapy was effective for treating a murine malignant melanoma cell line in vitro and in vivo. Sci Rep 6:30689. https://doi.org/10.1038/srep30689
Overgaard J (2007) Hypoxic radiosensitization: adored and ignored. J Clin Oncol 25:4066–4074. https://doi.org/10.1200/JCO.2007.12.7878
Overgaard J, Eriksen JG, Nordsmark M et al (2005) 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 6:757–764. https://doi.org/10.1016/S1470-2045(05)70292-8
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. https://doi.org/10.1002/stem.318
Pan F, Mao H, Bu F et al (2017) Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma. Oncotarget 8:5735–5752. https://doi.org/10.18632/oncotarget.13902
Park HJ, Griffin RJ, Hui S et al (2012) Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 177:311–327. https://doi.org/10.1667/rr2773.1
Patil M, Pabla N, Dong Z (2013) Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell Mol Life Sci 70:4009–4021. https://doi.org/10.1007/s00018-013-1307-3
Paul MK, Mukhopadhyay AK (2004) Tyrosine kinase—role and significance in cancer. Int J Med Sci 1:101–115. https://doi.org/10.7150/ijms.1.101
Pawlik TM, Keyomarsi K (2004) Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol 59:928–942. https://doi.org/10.1016/j.ijrobp.2004.03.005
Pedroza-Torres A, Campos-Parra AD, Millan-Catalan O et al (2018) MicroRNA-125 modulates radioresistance through targeting p21 in cervical cancer. Oncol Rep 39:1532–1540. https://doi.org/10.3892/or.2018.6219
Peitzsch C, Perrin R, Hill RP et al (2014) Hypoxia as a biomarker for radioresistant cancer stem cells. Int J Radiat Biol 90:636–652. https://doi.org/10.3109/09553002.2014.916841
Peitzsch C, Tyutyunnykova A, Pantel K, Dubrovska A (2017) Cancer stem cells: the root of tumor recurrence and metastases. Semin Cancer Biol 44:10–24. https://doi.org/10.1016/j.semcancer.2017.02.011
Pelloski CE, Mahajan A, Maor M et al (2005) YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11:3326–3334. https://doi.org/10.1158/1078-0432.CCR-04-1765
Peltola K, Hollmen M, Maula S-M et al (2009) Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor. Neoplasia 11:629–636. https://doi.org/10.1593/neo.81038
Perillo B, Di Donato M, Pezone A et al (2020) ROS in cancer therapy: the bright side of the moon. Exp Mol Med 52:192–203. https://doi.org/10.1038/s12276-020-0384-2
Petrelli NJ, Shaw N, Bhargava A et al (1988) Squamous cell carcinoma antigen as a marker for squamous cell carcinoma of the anal canal. J Clin Oncol 6:782–785. https://doi.org/10.1200/JCO.1988.6.5.782
Podralska M, Ciesielska S, Kluiver J et al (2020) Non-coding RNAs in cancer radiosensitivity: micrornas and lncRNAs as regulators of radiation-induced signaling pathways. Cancers (basel). https://doi.org/10.3390/cancers12061662
Pottier C, Fresnais M, Gilon M et al (2020) Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers (basel) 12:731. https://doi.org/10.3390/cancers12030731
Qin C-J, Song X-M, Chen Z-H et al (2015) XRCC2 as a predictive biomarker for radioresistance in locally advanced rectal cancer patients undergoing preoperative radiotherapy. Oncotarget 6:32193–32204. https://doi.org/10.18632/oncotarget.4975
Qu C, Zhao Y, Feng G et al (2017) RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma. J Cell Mol Med 21:2872–2883. https://doi.org/10.1111/jcmm.13200
Rajkumar T, Vijayalakshmi N, Sabitha K et al (2009) A 7 gene expression score predicts for radiation response in cancer cervix. BMC Cancer 9:365. https://doi.org/10.1186/1471-2407-9-365
Rivero M, Peinado-Serrano J, Muñoz-Galvan S et al (2018) MAP17 (PDZK1IP1) and pH2AX are potential predictive biomarkers for rectal cancer treatment efficacy. Oncotarget 9:32958–32971. https://doi.org/10.18632/oncotarget.26010
Rødningen OK, Overgaard J, Alsner J et al (2005) Microarray analysis of the transcriptional response to single or multiple doses of ionizing radiation in human subcutaneous fibroblasts. Radiother Oncol J Eur Soc Ther Radiol Oncol 77:231–240. https://doi.org/10.1016/j.radonc.2005.09.020
Saigusa S, Toiyama Y, Tanaka K et al (2010) Stromal CXCR4 and CXCL12 expression is associated with distant recurrence and poor prognosis in rectal cancer after chemoradiotherapy. Ann Surg Oncol 17:2051–2058. https://doi.org/10.1245/s10434-010-0970-y
Saigusa S, Toiyama Y, Tanaka K et al (2011) Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy. Int J Oncol 38:655–663. https://doi.org/10.3892/ijo.2011.906
Sakakura C, Miyagawa K, Fukuda K-I et al (2007) Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis. Oncogene 26:5927–5938. https://doi.org/10.1038/sj.onc.1210403
Sharda A, Rashid M, Shah SG et al (2020) Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells. Clin Epigenetics 12:4. https://doi.org/10.1186/s13148-019-0800-4
Shih S-C, Robinson GS, Perruzzi CA et al (2002) Molecular profiling of angiogenesis markers. Am J Pathol 161:35–41. https://doi.org/10.1016/S0002-9440(10)64154-5
Shrivastav M, De Haro LP, Nickoloff JA (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134–147. https://doi.org/10.1038/cr.2007.111
Sjöström M, Veenstra C, Holmberg E et al (2020) Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery: a long-term follow-up of the SweBCG91-RT randomised trial. Mol Oncol 14:2713–2726. https://doi.org/10.1002/1878-0261.12803
Skinner HD, Giri U, Yang L et al (2016) Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. Clin Cancer Res 22:4643–4650. https://doi.org/10.1158/1078-0432.CCR-15-2785
Snitcovsky I, Leitão GM, Pasini FS et al (2009) Plasma osteopontin levels in patients with head and neck cancer undergoing chemoradiotherapy. Arch Otolaryngol Head Neck Surg 135:807–811. https://doi.org/10.1001/archoto.2009.103
Stakheyeva M, Riabov V, Mitrofanova I et al (2017) Role of the immune component of tumor microenvironment in the efficiency of cancer treatment: perspectives for the personalized therapy. Curr Pharm Des 23:4807–4826. https://doi.org/10.2174/1381612823666170714161703
Suh Y-E, Raulf N, Gäken J et al (2015) MicroRNA-196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance. Int J Cancer 137:1021–1034. https://doi.org/10.1002/ijc.29397
Sui X, Jiang L, Teng H et al (2021) Prediction of clinical outcome in locally advanced non-small cell lung cancer patients treated with chemoradiotherapy by plasma markers. Front Oncol 10:625911. https://doi.org/10.3389/fonc.2020.625911
Sun G, Hu W, Lu Y, Wang Y (2013) A meta-analysis of HIF-1α and esophageal squamous cell carcinoma (ESCC) risk. Pathol Oncol Res 19:685–693. https://doi.org/10.1007/s12253-013-9631-3
Suzuki Y, Shirai K, Oka K et al (2007) Prognostic impact of pAkt in glioblastoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 69:S239–S240. https://doi.org/10.1016/j.ijrobp.2007.07.1235
Swanton C, Marcus S, Jayamohan J et al (2021) Can adjuvant pelvic radiation therapy after local excision or polypectomy for T1 and T2 rectal cancer offer an alternative option to radical surgery? Clin Transl Radiat Oncol 31:97–101. https://doi.org/10.1016/j.ctro.2021.10.002
Swartz JE, Wegner I, Noorlag R et al (2021) HIF-1a expression and differential effects on survival in patients with oral cavity, larynx, and oropharynx squamous cell carcinomas. Head Neck 43:745–756. https://doi.org/10.1002/hed.26530
Tang L, Wei F, Wu Y et al (2018) Role of metabolism in cancer cell radioresistance and radiosensitization methods. J Exp Clin Cancer Res 37:87. https://doi.org/10.1186/s13046-018-0758-7
Tay W-L, Yip GW-C, Tan P-H et al (2009) Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer. Mod Pathol 22:282–290. https://doi.org/10.1038/modpathol.2008.181
Tu Z, Xu B, Qu C et al (2015) BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro. Radiat Oncol 10:123. https://doi.org/10.1186/s13014-015-0427-3
Turner BC, Haffty BG, Narayanan L et al (1997) Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57:3079–3083
Venkatesh V, Nataraj R, Thangaraj GS et al (2018) Targeting notch signalling pathway of cancer stem cells. Stem Cell Investig 5:5. https://doi.org/10.21037/sci.2018.02.02
Vergis R, Corbishley CM, Norman AR et al (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9:342–351. https://doi.org/10.1016/S1470-2045(08)70076-7
Wang L, Pino-Lagos K, de Vries VC et al (2008) Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A 105:9331–9336. https://doi.org/10.1073/pnas.0710441105
Wang R, Ye F, Zhen Q et al (2016) MicroRNA-148b is a potential prognostic biomarker and predictor of response to radiotherapy in non-small-cell lung cancer. J Physiol Biochem 72:337–343. https://doi.org/10.1007/s13105-016-0485-5
Wang Y, Gan G, Wang B et al (2017) Cancer-associated fibroblasts promote irradiated cancer cell recovery through autophagy. EBioMedicine 17:45–56. https://doi.org/10.1016/j.ebiom.2017.02.019
Wang H-C, Chou C-L, Yang C-C et al (2019a) Over-expression of CHD4 Is an independent biomarker of poor prognosis in patients with rectal cancers receiving concurrent chemoradiotherapy. Int J Mol Sci. https://doi.org/10.3390/ijms20174087
Wang H, Jiang H, Van De Gucht M, De Ridder M (2019b) Hypoxic radioresistance: can ROS be the key to overcome It? Cancers (basel) 11:112. https://doi.org/10.3390/cancers11010112
Wang Y, Kim TH, Fouladdel S et al (2019c) PD-L1 expression in circulating tumor cells increases during radio(chemo)therapy and indicates poor prognosis in non-small cell lung cancer. Sci Rep 9:566. https://doi.org/10.1038/s41598-018-36096-7
Wang Z, Zhang J, Li M et al (2020) The expression of p-p62 and nuclear Nrf2 in esophageal squamous cell carcinoma and association with radioresistance. Thorac Cancer 11:130–139. https://doi.org/10.1111/1759-7714.13252
Willers H, Azzoli CG, Santivasi WL, Xia F (2013) Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer. Cancer J 19:200–207. https://doi.org/10.1097/PPO.0b013e318292e4e3
Wu X-Y, Wu Z-F, Cao Q-H et al (2014) Insulin-like growth factor receptor-1 overexpression is associated with poor response of rectal cancers to radiotherapy. World J Gastroenterol 20:16268–16274. https://doi.org/10.3748/wjg.v20.i43.16268
Wu Q, Allouch A, Martins I et al (2017) Macrophage biology plays a central role during ionizing radiation-elicited tumor response. Biomed J 40:200–211. https://doi.org/10.1016/J.BJ.2017.06.003
Wu C, Guo E, Ming J et al (2020) Radiation-induced DNMT3B promotes radioresistance in nasopharyngeal carcinoma through methylation of p53 and p21. Mol Ther Oncolytics 17:306–319. https://doi.org/10.1016/j.omto.2020.04.007
Xie P, Li X, Tan X et al (2016) Sequential serum Let-7 Is a novel biomarker to predict accelerated reproliferation during fractional radiotherapy in lung cancer. Clin Lung Cancer 17:e95–e101. https://doi.org/10.1016/j.cllc.2016.03.010
Xie F, Dong D, Du N et al (2019) An 8-gene signature predicts the prognosis of cervical cancer following radiotherapy. Mol Med Rep 20:2990–3002. https://doi.org/10.3892/mmr.2019.10535
Xu J, Escamilla J, Mok S et al (2013) CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73:2782–2794. https://doi.org/10.1158/0008-5472.CAN-12-3981
Yagi H, Danno K, Maruguchi Y et al (1987) Significance of squamous cell carcinoma (SCC)-related antigens in cutaneous SCC. A Preliminary Report. Arch Dermatol 123:902–906
Yang Z, Liu Z (2020) Potential functional variants in DNA repair genes are associated with efficacy and toxicity of radiotherapy in patients with non-small-cell lung cancer. J Oncol 2020:3132786. https://doi.org/10.1155/2020/3132786
Yang S-S, Yu D-Y, Du Y-T et al (2020) Inhibition of Delta-like Ligand 4 enhances the radiosensitivity and inhibits migration in cervical cancer via the reversion of epithelial-mesenchymal transition. Cancer Cell Int 20:344. https://doi.org/10.1186/s12935-020-01434-1
Yao Y-F, Du C-Z, Chen N et al (2014) Expression of HER-2 in rectal cancers treated with preoperative radiotherapy: a potential biomarker predictive of metastasis. Dis Colon Rectum 57:602–607. https://doi.org/10.1097/DCR.0000000000000107
Yin M, Liao Z, Huang Y-J et al (2011) Polymorphisms of homologous recombination genes and clinical outcomes of non-small cell lung cancer patients treated with definitive radiotherapy. PLoS ONE 6:e20055–e20055. https://doi.org/10.1371/journal.pone.0020055
Yoon MS, Nam T-K, Lee J-S et al (2011) VEGF as a predictor for response to definitive chemoradiotherapy and COX-2 as a prognosticator for survival in esophageal squamous cell carcinoma. JKMS 26:513–520. https://doi.org/10.3346/jkms.2011.26.4.513
Yoshida K, Suzuki S, Sakata J et al (2018) The upregulated expression of vascular endothelial growth factor in surgically treated patients with recurrent/radioresistant cervical cancer of the uterus. Oncol Lett 16:515–521. https://doi.org/10.3892/ol.2018.8610
Yoshimura Y, Oka M, Harada T (1990) Squamous cell carcinoma-antigen for detection of squamous cell and mucoepidermoid carcinoma after primary treatment: a preliminary report. J Oral Maxillofac Surg 48:1283–1288. https://doi.org/10.1016/0278-2391(90)90484-j
You G-R, Cheng A-J, Lee L-Y et al (2019) Prognostic signature associated with radioresistance in head and neck cancer via transcriptomic and bioinformatic analyses. BMC Cancer 19:64. https://doi.org/10.1186/s12885-018-5243-3
Yu T-K, Bhosale PR, Crane CH et al (2008) Patterns of locoregional recurrence after surgery and radiotherapy or chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 71:1175–1180. https://doi.org/10.1016/j.ijrobp.2007.11.018
Zhang W, Xu J (2017) DNA methyltransferases and their roles in tumorigenesis. Biomark Res 5:1. https://doi.org/10.1186/s40364-017-0081-z
Zhang H, Xie C, Yue J et al (2017a) Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFβ1 signaling loop in esophageal squamous cell carcinoma. Mol Carcinog 56:1150–1163. https://doi.org/10.1002/mc.22581
Zhang Y, Dong S, Xu R et al (2017b) Prognostic and predictive role of COX-2, XRCC1 and RASSF1 expression in patients with esophageal squamous cell carcinoma receiving radiotherapy. Oncol Lett 13:2549–2556. https://doi.org/10.3892/ol.2017.5780
Zhang G, Zhang K, Li C et al (2019) Serum proteomics identify potential biomarkers for nasopharyngeal carcinoma sensitivity to radiotherapy. Biosci Rep. https://doi.org/10.1042/BSR20190027
Zhang M, Zhang L, Hei R et al (2021) CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res 11:1913–1935
Zhao L, Tang M, Hu Z et al (2015) miR-504 mediated down-regulation of nuclear respiratory factor 1 leads to radio-resistance in nasopharyngeal carcinoma. Oncotarget 6:15995–16018. https://doi.org/10.18632/oncotarget.4138
Zhao J, Zhang P, Wang J et al (2017) Plasma levels of soluble programmed death ligand-1 may be associated with overall survival in nonsmall cell lung cancer patients receiving thoracic radiotherapy. Medicine (baltimore) 96:e6102–e6102. https://doi.org/10.1097/MD.0000000000006102
Zheng Q, Ding H, Wang L et al (2021) Circulating exosomal miR-96 as a novel biomarker for radioresistant non-small-cell lung cancer. J Oncol. https://doi.org/10.1155/2021/5893981
Zhou Y, Chu L, Wang Q et al (2018) CD59 is a potential biomarker of esophageal squamous cell carcinoma radioresistance by affecting DNA repair. Cell Death Dis 9:887. https://doi.org/10.1038/s41419-018-0895-0
Zhu P, Ou Y, Dong Y et al (2016) Expression of VEGF and HIF-1α in locally advanced cervical cancer: potential biomarkers for predicting preoperative radiochemotherapy sensitivity and prognosis. Onco Targets Ther 9:3031–3037. https://doi.org/10.2147/OTT.S104142
Zlobec I, Vuong T, Compton CC et al (2008) Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 98:450–456. https://doi.org/10.1038/sj.bjc.6604172
Zou Z, Chang H, Li H, Wang S (2017) Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis 22:1321–1335. https://doi.org/10.1007/s10495-017-1424-9
Acknowledgements
No funds, grants, or other support were received.
Funding
No funding was secured for this manuscript.
Author information
Authors and Affiliations
Contributions
IL and ED had the idea for the article, IL, MR, EI and YT performed the literature search and data analysis, IL, AC and ED drafted and critically revised the work.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Larionova, I., Rakina, M., Ivanyuk, E. et al. Radiotherapy resistance: identifying universal biomarkers for various human cancers. J Cancer Res Clin Oncol 148, 1015–1031 (2022). https://doi.org/10.1007/s00432-022-03923-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-022-03923-4