Epithelial mesenchyme transition in cancer cells

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Published: 18 Jul 2012
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Prof Jean-Paul Thiery – Institute of Molecular and Cell Biology, Singapore

Prof Jean-Paul Thiery discusses the reversible transition of tumour cells from an epithelial to a mesenchyme state and explains the potential role that targeting this transition could play in cancer therapy. The epithelial mesenchyme transition is necessary for tumours to successfully metastasise, and following new research recording the development of cancer cells it is now known that this occurs at a very early stage in cancer development. Mesenchyme-like cells have a very high chemo-resistance and consequently Prof Thiery’s research establishes the need for cancer therapies designed to restore cell chemo-sensitivity.

22nd European Association for Cancer Research, Barcelona, 8th July 2012

 

Epithelial mesenchyme transition in cancer cells

 

Professor Jean-Paul Thiery – Institute of Molecular and Cell Biology, Singapore

 

Dr Thiery, we’re here at EACR in Barcelona and for a long time you’ve been involved in the epithelial mesenchyme transition and its involvement in cancer. Can you discuss a bit about this?

 

Yes. Basically, epithelial mesenchymal transition is a mechanism of absolute importance in development for all organisms. From the most primitive species to man, that is to say from jellyfish to man, you need to have this mechanism operating to create the body plan. In other words, this is a mechanism by which an original epithelial layer will momentarily and locally transform into a migratory cell we call a mesenchyme. So this mechanism operates in many different parts of the embryo, it operates very early, it operates later. The cardiac structures form through four cycles of epithelial mesenchymal transition so you can easily understand that any defect in this process will lead to death or very severe malformations.

 

Now when I was studying these mechanisms in embryos, I saw that perhaps cancer cells, a carcinoma, which are most tumours in humans probably could have co-opted some of these mechanisms to try to locally invade and, most importantly, disseminate in a different part of the body. In other words, the carcinoma cells are epithelial-like cells that will somehow very locally de-differentiate into migratory mesenchymal-like cells which will acquire momentarily very invasive, aggressive properties able to reach blood vessels or lymphatics then disseminate through passive transport to distant sites. Then I made the hypothesis that when they would reach a target site, they will resume their epithelial phenotype. In other words, this mechanism is reversible in nature and so you go from an epithelial state to a very transient mesenchymal-like state and then finally regain your epithelial-like state. So, in fact, the metastatic tumours are often more differentiated than the primary tumours. That probably supports the idea that you have a reversal mechanism and so we want to exploit that in our therapeutic strategies that would be based on that concept.

 

Lots of people now in the world are working on some aspects of this epithelial mesenchymal transition from both the theoretical basic side, if you want, and even from the clinical side and particularly translational research, a lot of labs somehow utilise this concept. So originally, obviously, a number of people were quite refractory to that idea that cells would undergo these transitions and, as I say, these reversible transitions because to capture that phenomenon is, for pathologists, the hardest time in the past. Using simple haematoxylin and eosin stains in just straightforward pathology, they would have a hard time to capture this very precise moment where the cell would execute this transition. Now, obviously, with a number of antibodies and a lot more characterisations of the mechanisms, we now are able to see them. Obviously they are not a massive… sometimes a massive transformation is sometimes very local and so this is why you have to pay great attention when you look at histopathology studies to really detect those cells.

 

Obviously we cannot film them in humans but we can film them in models, in murine models people have been able to film the cell exiting the primary tumour, single cells, migratory single cells; they are able to follow them up to the blood vessels, they can see them intravasating. It’s a bit harder to see them extravasating at the secondary sites because we cannot really film that so easily but now we have at least a good idea of how does that occur, when does that occur and in carcinoma, as I said, 90% of human tumours, these mechanisms operate probably quite early in the development of the tumour. In other words, you are going to form what we call micrometastases very early, that is to say some tumour mass below 1cm diameter, 1 cm3 volume, would already deliver some cells in the periphery. This is a very frightening process because obviously by clinical studies people would consider those tumours are not immensely aggressive and with a low chance of recurring, however, it’s not a 100% cure. Even breast cancer 1 cm3 tumour has a 5-7% chance to recur. So this is indeed linked to the presence of undetectable micrometastases that are already disseminated in different organs including the bone marrow or other sites like the liver, the lung and potentially the brain as well. So clearly this is what kills the patients at the end.

 

So what we want to achieve here is obviously we are not probably going to be, in the short term, able to prevent this mechanism, we’re probably going to be too late when we treat the patients with anti-EMT drugs, but what we want to achieve for the moment is to try to restore some chemosensitivity. These particular cells that are mesenchymal-like are more resistant to chemotherapy and often they behave almost like stem cells, there are lots of papers characterising that and we will hear tomorrow something about it again. So clearly these are quite unique, the mesenchymal-like cells and they have very interesting features that we have to combat to try to regain something more differentiated. This is an old idea in some ways, in the past there were examples of erythroid leukaemias we were able to differentiate using even dimethyl sulfoxide which is a preservative, it is a solvent that we use to freeze cells. So it was a magic situation where erythroid leukaemias would transform into erythrocytes. More recently, myelocytic leukaemias can be differentiated using retinoic acid or arsenite and there’s a bunch of other examples like that that are rare but meaningful. So we hope that by playing with the epithelial mesenchymal transition driven pathways we would be able to interfere with these mechanisms and render these cells more susceptible to chemo and potentially prolong the life of cancer patients.

 

I think this is a relatively new era in the field of cancer. In 2000 there were probably no more than 100 publications, a lot of them from me, but now we have about 5,000 publications at least and I think lots of people, even though they may not be completely convinced, have already considered in their studies this particular mechanism. So it takes a long time to convince colleagues but I think now there’s ample evidence published in very good journals by many other people than me, including Bob Weinberg and many others in the field that got somehow interested with these mechanisms.

 

OK, thank you.