Mechanisms of the tumour microenvironment and inflammation

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Published: 20 Nov 2012
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Dr Alberto Mantovani – University of Milan, Italy

Discussing his talk on the mechanisms linking inflammation and cancer, Dr Mantovani highlights the importance of the tumour microenvironment at the IFOM-Kyoto University Joint Symposium in Milan. 

 

Dr Mantovani notes that a tumour is not only made up tumour cells, but also normal cells that provide structure, blood vessels and defense cells, such as macrophages. The key to fighting the tumour cells and inflammation is reprogramming the defense cells to recognise the tumour cells as negative.

The microenvironment of tumour cells is of paramount importance. In a way we are rediscovering the ecology of cancer. So a tumour is made not only of tumour cells, where the genetic events occur or occurred, but it’s also made of normal cells which provide stroma, so the structure, the general architecture, the blood vessels which provide nutrients and so on and of defence cells, macrophages in particular which are dear to my heart. What happens in tumours, we have come to realise that in established tumours defence cells, immune cells, behave like corrupted policeman. In other words, they get corrupted and they provide tools, they help tumour cells to grow. They promote angiogenesis, they stimulate metastatic dissemination. So one of the frontiers is stop the policemen, the corrupted policemen, and re-educate the defence cells to do their job against tumour cells.

How does this involve the repelling factors?

There are signals that are coming from tumour cells themselves. In the Darwinian evolution of tumours tumour cells produce mediators which change the orientation, the functional orientation, of macrophages, for instance, from macrophages geared to killing tumour cells to macrophages geared to promoting tumour growth.

Could you talk a little about the micro-antibodies?

There are factors, well actually tumour cells… I also did work thirty years ago, we had a science paper more than thirty years… it will be thirty years ago next year. Because, of course, we had the idea, we had data actually, not the idea, that macrophages were corrupt policemen that were helping tumour growth which went against current wisdom of the time. We reasoned that if that was the case there should be attractive factors produced by tumour cells to help macrophages come in and help tumour growth. So we described what, at the time, we called tumour-derived chemotactic factors which turned out to be what we call chemokines. Chemokines are a huge superfamily, 46 genes in man, which orchestrate the trafficking of macrophages. Chemokines are a component of the ecology of cancer, of the tumour microenvironment.

Can you stop the inflammatory response?

Absolutely, absolutely. So currently, on the one hand, we as a community and we as our own group, we are developing strategies to kill the corrupted policemen, for instance macrophages in particular in our own case, and we have proof of principle of that in the clinic, to stop their coming in. And, on the other hand, there is very strong data now showing that one can reactivate the dormant tumour system, the approved usage in the US of anti-CTLA4 antibodies and the very promising recent data on anti-PD1 and anti-PDL1 which were recently published in New England. Actually we have here Honjo who was the one who originally discovered PD1 and PDL1.

Are there any other drugs you are looking at?

We have been thinking of that. Years ago and I organised a meeting in London, by the way. At the time our statement, and we had a reader in The Lancet dating back to . Apart from the basic science and the clinical correlations we had a question and the question was should we all take aspirin? Or many of us, should we take aspirin? We had epidemiologists and the answer was no, definitely not. Particularly, for instance, studies such as the Framingham Study suggested no. Now we have a no with many question marks, I would say, because all the data coming from the pooled analysis, what in our jargon we call the meta-analysis, of all the clinical trials that have been done with aspirin provide compelling evidence for prevention of cancer, of many cancers, and prevention of metastases. So in my own attitude I will tell you what I say. I don’t take aspirin. When I take aspirin I think, well, it may help me fight cancer and when I have a friend who takes aspirin because of cardiovascular problems I say, well, look, it might help you fight cancer. That’s my present attitude.