In order to progress beyond a certain size, tumours need to develop their own blood supply for nutrients and oxygen.
Figure 1: Hypoxic regions occur in most of not all solid tumours. (A) HCT116 cells (human, colorectal) were grown as a tumour xenograft to an approximate diameter of 8 mm. Prior to sacrifice animals were injected with 60 mg/kg pimonidazole. The hypoxic regions were then visualised by immunohistochemical staining of pimonidazole (brown). Nuclei were counterstained with hematoxylin. (B) An enlarged tumour region from (A) showing a hypoxic area and blood vessels (~ 70-200 μm). Necrotic regions were also identified beyond the hypoxic regions.
Although tumours are able to create their own blood supply this process is not perfect and so tumours have regions which do not receive enough oxygen. Hypoxia is the term used to describe any situation where there is insufficient oxygen. Most solid tumours have regions of hypoxia, which is significant because many studies have shown that the more hypoxic a tumour is, the worse the patient does. Importantly, this is independent of the therapy type the patient receives. Hypoxic tumours are resistant to both chemotherapy and radiotherapy as well as being more likely to spread and are therefore the most aggressive and hardest to treat. To improve the effectiveness of cancer therapy it is vital that we target the hypoxic part of tumours. Our group has three approaches to this problem:
- We are investigating the biological response to hypoxia and in particular a pathway known as the DNA damage response. This pathway is active in hypoxic conditions despite a lack of detectable hypoxia-induced DNA damage. There are many drugs to target this pathway and it is possible that they will prove particularly useful in killing hypoxic cells when combined with standard therapies such as radiation.
- We are developing novel drugs which only work in the absence of oxygen and so can be used to target the hypoxic areas of tumours. This approach allows us to use potentially toxic drugs as the normal cells in the body are unaffected.
- Finally, it is vital that novel inhibitors/drugs are tested in conditions which mimic those found in tumours. Therefore, we test drugs in conditions which more closely resemble those found in tumours, including low oxygen, to determine if they are likely to be effective.
Figure 2: Hypoxia leads to severely compromised activity of Ribonucleotide reductase (RNR) due to the oxygen dependency of the RRM2 subunit, which leads to replication stress. The stress-responsive subunit, RRM2B is then induced through the DNA damage response (DDR) pathway to maintain on-going replication. RRM2B is able to retain activity in hypoxic conditions compared to RRM2. However, insufficient dNTPs are generated by RNR composed of RRM1/RRM2B and therefore replication stress is unresolved and persists. The importance of RRM2B activity is that whilst it does not resolve replication stress, it does maintain replication fork integrity and prevents the accumulation of DNA damage and loss of genome stability. Foskolou et al., Mol Cell 2017