Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

Abstract

The hypoxic tumour is a chaotic landscape of struggle and adaption. Against the adversity of oxygen starvation, hypoxic cancer cells initiate a reprogramming of transcriptional activities, allowing for survival, metastasis and treatment failure. This makes hypoxia a crucial feature of aggressive tumours. Its importance, to cancer and other diseases, was recognised by the award of the 2019 Nobel Prize in Physiology or Medicine for research contributing to our understanding of the cellular response to oxygen deprivation. For cancers with limited treatment options, for example those that rely heavily on radiotherapy, the results of hypoxic adaption are particularly restrictive to treatment success. A fundamental aspect of this hypoxic reprogramming with direct relevance to radioresistance, is the alteration to the DNA damage response, a complex set of intermingling processes that guide the cell (for good or for bad) towards DNA repair or cell death. These alterations, compounded by the fact that oxygen is required to induce damage to DNA during radiotherapy, means that hypoxia represents a persistent obstacle in the treatment of many solid tumours. Considerable research has been done to reverse, correct or diminish hypoxia’s power over successful treatment. Though many clinical trials have been performed or are ongoing, particularly in the context of imaging studies and biomarker discovery, this research has yet to inform clinical practice. Indeed, the only hypoxia intervention incorporated into standard of care is the use of the hypoxia-activated prodrug Nimorazole, for head and neck cancer patients in Denmark. Decades of research have allowed us to build a picture of the shift in the DNA repair capabilities of hypoxic cancer cells. A literature consensus tells us that key signal transducers of this response are upregulated, where repair proteins are downregulated. However, a complete understanding of how these alterations lead to radioresistance is yet to come.

Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia

“…According to the oxygen fixation hypothesis, the presence of oxygen makes these damages very difficult for the cell to repair (i.e., oxygen “fixes” the damage). Therefore, DNA damage induced in the presence of hypoxia is 2.5–3 times less likely to end in cell death [ 59 ]. Hypoxia-induced chemoresistance may be mediated by several factors, including the induction of various genes controlling cell metabolism and survival [ 3 ] as well as induction of stemness [ 60 ].…”

Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter

“…Activation was independent on HIF1A [ 123 ]; however, chromatin modification may be involved [ 128 ]. In addition, DNA repair pathways, including homologous recombination (HR) and non-homologous end-joining, are downregulated at severe hypoxia [ 129 ], possibly due to lack of repair proteins [ 123 ]. Hence, prolonged (48 h) exposure of cells to 0.01% O 2 induced a 6-fold decrease in expression of the HR repair protein RAD51 that was apparent also at 0.5% O 2 and accompanied by a decrease in HR [ 130 ].…”

Advances in Hypofractionated Irradiation-Induced Immunosuppression of Tumor Microenvironment

“…High dose irradiation induces tumor vascular damage, which limits the infiltration of cytotoxic T lymphocytes into the tumor and increases the area of hypoxia ( 82 , 83 ), leading to the resistance to radiotherapy ( 84 , 85 ). Tumor blood vessels are more permeable and morphologically immature, and they are more sensitive to radiation ( 86 ).…”