AACR 2016

Inflammatory microenvironment regulates colorectal cancer progression

Dr Sergei Grivennikov - Fox Chase Cancer Center, Philadelphia, USA

I came to AACR to report on our latest findings in the area of inflammation and cancer, particularly our lab is interested to find molecular mechanisms of how chronic unresolved inflammation promotes tumour growth and progression with the hope in the future that other scientists will be able to bring it to clinical and translational implications.

Could you summarise your talk?

There are many types of inflammation associated with tumour development and we particularly are interested in studying one of them which is called tumour released inflammation and which has been characterised only recently. That is a type of inflammation which normally does not exist at the time when the tumour is formed but as the tumour grows somehow, magically, it gets the abilities to recruit immune cells and activate inflammatory mediators similarly for the benefit of the tumour. We try to study how particular cytokines, small molecular mediators released by cancer cells or by immune cells, can act to promote inflammation and to promote tumour growth.

Why use inflammation to promote tumour progression?

Inflammation is needed to fight infection but also it is needed for correct wound healing and resolution of infection because very often infection happens via our epithelial barriers and if those epithelial barriers are breached then bacteria or viruses can get in and cause a disease. So when the immune system is poised to take care about those bacteria or viruses it also tries to restore those functional epithelial barriers or borders to do correct wound healing. In the case of cancer, because of the oncogenes, because of the mutations of tumour suppressors, and in some cancers associated with a bacterial component, like colon cancer and gastrointestinal cancers, skin cancers, in this case the epithelial barrier and tissue homeostasis are severely disrupted and the immune system tries to restore this homeostasis by forcing epithelial or cancer cells to proliferate because the normal tissue probably would just result in closing down the epithelium and restoration of tissue homeostasis. But in cancer it only results in increased tumour growth and because of that it’s like a vicious cycle, like a feed-forward loop, so more cancer growth means more inflammation.

Is there a way to shut down the cycle?

For preventive measures people noticed for a long time that, for example, chronic usage of aspirin magically reduces cancer associated death. It was initially invented to help people with a high risk of heart disease but then it turned out that it protects against cancer much better than it protects against heart disease. So we already know that non-specifically targeting inflammation helps. Also we know that lifestyle and dietary changes also help to reduce chronic inflammation because many types of inflammation are associated with chronic environmental exposure, let’s say to toxins, to fine particles, asbestos, food poisoning as well as tobacco smoke or obesity associated inflammation which, by the way, are on the rise in the westernised world. So all those sorts of environmental stimuli which promote chronic inflammation could be targeted for interventions to basically prevent cancer because you can change your lifestyle or diet or any other factors influencing chronic inflammation in general.

Of course also we are talking about creation of new, more targeted therapies, so therapies to block inflammation in autoimmune diseases are already available. We know that we can block inflammatory bowel disease with a blocking cytokine called TNF or interleukin-1 that can block rheumatoid arthritis or multiple sclerosis. And theoretically, and it has been tested now on animal models and limitedly in clinical trials, the same in cytokines which we study can be potentially used in cancer as well. Maybe they can be brought to clinics much faster because their safety profile is already known from the studies in autoimmune diseases and models.

If the inflammation is shut down, does this pose a risk to the patient?

In general there will be such concern because, for example, even aspirin which is seemingly harmless often causes bleeding in gastrointestinal tissue. Any biological therapy or anything targeted at inflammation potentially will have some side effects but we strongly believe that side effects probably will not be comparable with the risk of dying from cancer or from any other severe autoimmune disease which is life-threatening.

What avenues are you looking at for future discoveries?

Targeting cytokines and inflammation unlikely will work as a monotherapy in advanced cancers but, as you mentioned indeed, for example one of the problems checkpoint inhibitors face is that they are quite effective in some cases but in other cases the tumour microenvironment does things like immunosuppression and particularly this immunosuppression is achieved by secretion of different cytokines which can participate in the chronic inflammation. So theoretically, and that remains to be tested, anti-cytokine blockade can be combined with checkpoint inhibitor blockade or, alternatively, can be combined with different chemotherapy or radiotherapeutic approaches. Very likely that combination will be more effective than just using conventional chemotherapy or conventional radiotherapy.

What is your take-home message?

We think that the entire field of tumour microenvironment, and particularly chronic inflammation, play a role in tumour development. Is a very exciting one, major progress in that field has been done probably in the last ten years and there are many, many more avenues to study and we are very excited that a lot of young researchers now join this subject of biological and biomedical science. Really that field holds a lot of promise for the future development either of preventive or therapeutic strategies for cancer but also for autoimmune disease.