The tumour-promoting activities of a famous protein
Developing new cancer therapies and a more reliable test for prostate cancer are just some of the potential outcomes of Maurice Wilkins Centre research into the cellular mechanisms that trigger aggressive forms of cancer.
The work of PhD student Imogen Roth and her colleagues, recently published in the international cancer journal Oncogene, delves into how a variant of the renowned cancer biology protein called “p53” causes particularly poor survival in cancer patients.
The gene that encodes p53 is the most commonly mutated gene in cancer. p53 normally acts to suppress cancer formation, so loss of p53 makes cells susceptible to becoming cancerous. What is often less appreciated is that there are several different isoforms of the p53 protein. One of these, known as Δ133p53, promotes cancer progression. The MWC team, led by principal investigator Professor Antony Braithwaite at the University of Otago, has been studying why.
Studies in mice demonstrated that Δ133p53 is a cancer-promoting gene or “oncogene”. Subsequent pathology revealed widespread inflammation and high levels of an inflammatory chemical messenger called Interleukin 6 (IL-6).
“If inflammation is sustained over a long period of time it can also be a driver of cancer,” says Antony. That led to further research to ask if IL-6 could promote the spread of cancer cells through the process known as metastasis.
The team concluded that Δ133p53 is a driver of metastasis, and that IL-6 is a major component of the cancer cells’ increased ability to invade other tissues. IL-6 also works in conjunction with CCL2, a chemical messenger responsible for making cells migrate. “So IL-6 is the switch and CCL2 is the effector of that migration” says Antony. “I think we’ve made the first link between the Δ133p53 isoform and inflammation that drives cancer."
Pathological examination of prostate cancers has also revealed that 30 per cent of cases have high levels of Δ133p53. The patients that have the poorest survival rates also have the highest levels of Δ133p53 and involvement of inflammatory cells, according to Antony.
As for future research, Antony hopes to “recreate” their mutant mouse within prostate cells that could answer questions about the role of Δ133p53 in prostate cancer. That, in turn, could lead to the development of specific therapies to prevent tumours.
Following completion of her PhD, Imogen was successful in obtaining a Nuffield Fellowship to Oxford where she is continuing to work on p53 and inflammation.
Thanks to the MWC, Antony says she received “really critical funding without which she would have never got to the point she is now.”