Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Abstract

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.

Hypoxia in Solid Tumors: How Low Oxygenation Impacts the “Six Rs” of Radiotherapy

“…Some of them were able to improve the local control of the tumor but appeared too difficult to set up in a clinical routine ( 131 ). More recently, several pre-clinical studies established a rationale for combining radiotherapy with HIF-1 inhibitor ( 132 , 133 ), leading, for example, to a phase I clinical trial using PX-478 in advanced solid tumors (NCT00522652).…”

Hypoxia in Lung Cancer Management: A Translational Approach

“…As a fibric acid derivative displacing oxygen from hemoglobin to hypoxic tissue ultimately leading to an increase of oxygen delivery, efaproxiral exhibited promising results in phase I/II but failed in the later phase of clinical development, especially as a radiosensitiser and hypoxic target therapies [ 374 , 375 , 376 ]. Several additional clinical trials are ongoing with novel radiosensitisers [ 377 , 378 ], and modified radiotherapy protocols according to the hypoxic region to enhance immune cytogenic anti-cancer effect [ 379 , 380 ].…”

Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer

“…For this reason, the dynamics of abnormal vessel growth that arise in tumor tissue due to angiogenesis [ 61 ] are not taken into account. Furthermore, it has been shown that radiation therapy can cause hypoxia [ 62 ] or upregulate HIF-1 expression [ 63 ], which in turn leads to a development and selection of more resistant cells [ 64 , 65 ]. Moreover, the biological effects induced by other pharmaceuticals, e.g., the effect of androgen-deprivation therapy with bicalutamide in selecting more resistant cells to the treatment [ 66 ], are not considered at this stage.…”