Cancer Grand Challenges is series of £20m ($25m) awards that give international teams of researchers the freedom to think differently, act creatively and explore truly innovative science to take on fundamental questions in cancer.
It is estimated that up to 50% of human cancer is caused by definable risk factors that could be avoided. When the steps that arise from exposure to a risk factor to cancer initiation are known, for example following exposure to UV or to tobacco smoke, this knowledge has been very important for prevention, diagnosis, and in some cases therapeutic intervention.
Inflammation is one of the most common biological stages following exposure to potential carcinogenic agents or conditions. Inflammation is characterised by a large number of cellular changes, and it is not known whether there are different functional subclasses of inflammation. Importantly, we do not know which of the many changes seen in inflammation are essential for increasing cancer risk. Identifying the critical steps that lead from inflammation to cancer initiation could provide points for cancer prevention and important markers for diagnosis of early stage cancer.
Barriers and opportunities
While inflammation is commonly reported in many biological conditions, the molecular characteristics that are directly causal for cancer initiation remain unclear. Inflammation frequently sets up oxidative conditions which can damage DNA, proteins, and lipids. Inflammation in some settings will stimulate repeated cell division with the associated potential for DNA mutation. Inflammatory conditions induce many changes in transcriptional programmes. In addition, increasing evidence points to immune dysfunction with ageing. Any of these or other associated changes could be integral for cancer initiation.
Teams will need to establish reproducible systems to induce inflammatory conditions that allow examination of characteristic changes as well as the ensuing recognisable stages of early cancer development. Variations in the types of inflammatory stimuli and the influence of ageing upon the immune response should be considered. These systems will need to represent various human tumour development settings and should correlate with changes seen in various tissue environments.
Successful teams will need to understand which of the changes seen in various precancerous lesions are key to the inflammatory process. Functional tests will be required to determine which of these changes are essential for subsequent steps in tumour development. It will be essential to determine whether there are recognisable downstream events emanating from inflammatory conditions that are required for cancer initiation.
Important questions that might be considered include but are not limited to:
- Do inflammatory markers change by tissue source or type of upstream stimulus?
- What is the timing of inflammation with unstoppable tumour initiation?
- Is there more than one type of inflammation?
- Can specific components of the inflammatory state be markers for the rate or severity of tumour development?
- How does the quality and potency of the immune response alter with ageing?
Vision and Impact
Success in answering this challenge would be to identify the causative events associated with inflammation that lead to cancer development in vivo. This could lead to new targets for cancer prevention or better use of existing interventions. Better systemic biomarkers could advance the diagnosis of early stages of cancer development or warn individuals of potentially dangerous advancing conditions.
To address this challenge will require a multidisciplinary team that may include epidemiology and cancer biology expertise.
Deeper understanding of how dangerous risk factors lead to cancer initiation will help us understand how this important but still mostly mysterious stage of cancer development occurs.