Abstract
Simple SummarySome regions of aggressive malignancies experience hypoxia due to inadequate blood supply. Cancer cells adapting to hypoxic conditions somehow become more resistant to radiation exposure and this decreases the efficacy of radiotherapy toward hypoxic tumors. The present review article helps clarify two intriguing points: why hypoxia-adapted cancer cells turn out radioresistant and how they can be rendered more radiosensitive. The critical molecular targets associated with intratumoral hypoxia and various approaches are here discussed which may be used for sensitizing hypoxic tumors to radiotherapy.Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.
Highlights
Radiation exposure is the significant modality to fight cancer, and most of patients with solid malignancies receive courses of photon or hadron therapy
Taking into consideration that it is Hypoxia-inducible factor-1 (HIF-1) that mediates the expression of hexokinase 2 (HK2), glucose transporter 1 (GLUT1) and pyruvate dehydrogenase kinase 1 (PDK1) and formation of the “Warburg phenotype” within hypoxic tumors [114,115], the inhibitory targeting of HIF-1α may abolish both the hypoxia-associated energy metabolism reprogramming in tumor cells and their high radioresistance conferred by this reprogramming
Taking into consideration all the reviewed data, one can conclude that the tumor cell response to chronic or prolonged hypoxia is a complex, multifactor and multilevel process that includes dramatic alterations in gene expression, signaling pathways, energy metabolism, epigenetic regulation, the work of chaperones, autophagy, secretory activity and other stress-sensitive mechanisms of the involved cancer cells
Summary
Radiation exposure is the significant modality to fight cancer, and most of patients with solid malignancies receive courses of photon or hadron therapy (reviewed in [1,2]). Antitumor radiotherapy is not always effective; in particular, the enhanced radioresistance is often exhibited by cancer cells within the hypoxic zones of tumors, and this is a great challenge [3,4]. Tumor cell-stimulated angiogenesis is one of the hallmarks of cancer [5], the aggressive malignancies usually contain poorly vascularized regions where the angiogenic. The exosome secretion by hypoxia-stressed cancer cells promotes their migration, invasion and metastasis spread (see Figure 2 and Section 9) Such hypoxia-driven generation of the actively migrating radioresistant CSC-like cells is conducive to the weak responsivity of hypoxic tumors to radiotherapy, since blood circulation allows these vasculaturepenetrating tumorigenic cells to flee the zone being exposed to therapeutic irradiat3ioofn (Figure 2). That is why additional (radiosensitizing) cotreatments may enhance the efficacy of high-LET radiation-based therapy toward hypoxic tumors. Scuemllumlaarribzainsigs aof latrhgeeraamdioournestiostfadnactea,otfhheypproesxeicntturemvoierws acnodnsaidlseorscrtihteicmalloyleecsutliamraatneds scoemlluelaarpbparsoiascohfetsheto rardadioioresseinsstaitnizcienogfchaynpceorxciceltlus minohrsypanoxdicaltsuomcorirtirceagliloyness.tTimheataeus tshoomrseoafptphrisoarecvhieeswtoadravdainoc-e seannsiidtiezainagbocuant ctheer cneelclessisnithyyopfocxoimc btuinmatoirvereagnidonms.uTlthitearaguetthtorerastomfetnhtiss irnevoiredweratdovoavnecrceoamne the radioresistance of hypoxic tumors
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
