BACR & ECMC: Therapeutic interventions for cancer prevention
COMMD1 pathway activated by aspirin restores apoptosis in colorectal cancer
Dr Lesley Stark - Edinburgh Cancer Research Centre, Edinburgh, UK
Obviously the conference is on the prevention of cancer. I have been working on the mechanisms by which aspirin prevents colorectal cancer for a number of years. What I explained was that the approach I use was to use cell line studies with higher doses of aspirin then to repeat these with much lower, more pharmacological doses of aspirin to look for those mechanisms that are absolutely required for the apoptotic effects of the agent and then to go into more ex vivo and in vivo models to look at the translational aspect. What we have found from those studies is a network that’s important for aspirin prevention of colorectal cancer that is focussed around the NF kappa-B signalling pathway. NF kappa-B is active in the majority of cancer and it drives carcinogenesis. What we have found is that aspirin actually activates the NF kappa-B pathway but rather than causing an increase in NF kappa-B driven transcription it actually represses transcription so it switches off NF kappa-B activity which causes the induction of apoptosis.So the protein that I talked most about was a protein called COMMD1 which actually is the protein that switches off NF kappa-B activity.
Are there any cross-applications with different tumour sites?
People have shown that COMMD1 is reduced in a number of different cancers. So what I initially found was that aspirin actually increases the level of COMMD1 in colorectal cancers. At the same time I was studying the aspirin effects on COMMD1 a study came out saying that this protein was actually reduced in a number of different cancer types and that the reduction of COMMD1 was associated with reduced survival and increased metastasis. So because of the effects of aspirin on the protein we decided to look at what COMMD1 was doing in colorectal tumours using immunohistochemistry with matched colorectal cancers and normal controls, a tissue microarray of 118 colorectal tumours of Dukes’ A and B and we looked at cancer polyps as well where there are areas of normal mucosa adenoma and invasive cancer. With all those studies we could show that COMMD1 levels were actually reduced in colorectal cancer and that reduction in the more aggressive areas of the cancer and in more aggressive type of cancers. So it would suggest that like the other cancers that were published that COMMD1 is reduced in colorectal cancer and it’s helping to drive the cancer progression. What we’ve shown is that aspirin increases those levels so that might be how it’s actually working.
What are you working on next?
What I would like to do is be able to get hold of material from some of the other people who are at this conference. Because what I would like to be able to do is actually look to see whether the aspirin causes an increase in COMMD1 in human material from patients who have been given aspirin in trials and whether the initial level of COMMD1 can predict whether they have a response to aspirin or not or whether aspirin causes a change in levels of that protein. So, yes, that’s what I would like to do going forward and at much lower doses.