European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Influence of regenerative stem cells and cell microenvironment upon treatment success

Dr Brad Wouters – Ontario Institute for Cancer Research, Toronto, Canada

Brad Wouters from Princess Margaret in Toronto, you were talking a little bit ago about stem cells and this interesting stuff that’s going to come up in the ESTRO meeting next May. I hadn’t thought before that the radiation biologists would be interested in stem cells, normal stem cells for regeneration, I thought the surgeons might be but I hadn’t thought that the radiation people would be.

Yes, certainly they are. The effective dose that we can deliver to patients, despite having very sophisticated treatment delivery approaches, is still determined by normal tissue toxicities that arise and dose limitations. There are certain tissues where we can potentially get around those barriers of dose limitation if we could provide regenerative approaches and this is being attempted, for example, in salivary glands which limit the dose in many types of head and neck cancer treatment. Groups in the Netherlands, Rob Kopp’s group in the Netherlands has isolated at least early progenitor cells for those tissues for developing potentially new salivary glands. So we’re able to, as a field, build upon a lot of the research that’s going on now in this area for various type of diseases but certainly this can include damage caused by radiation to normal tissues as well.

I think people who have never had a dry mouth do not understand what a terrible thing it is and what a real negative effect it has on your quality of life, that’s very interesting.

Absolutely.

And then cancer stem cells? I thought by definition they were radioresistant?

It’s a bit debated, there certainly are publications and demonstrations where they can be radiation resistant.

They are chemoresistant, we’re agreed on that.

And many of them are also chemoresistant and, of course, in curative settings like radiation oncology, the experience with patients on radiosensitivity is governed by cells that ultimately matter and which ultimately determine long-term response to therapy. So our understanding of radiation sensitivity really reflects the cells of importance in the tumour, the tumour stem cells. These stem cells, of course, have their own biological properties and one of our interests in my lab is understanding the importance of tumour hypoxia which is a common feature of solid tumours. I don’t do a lot of research on stem cells myself but the microenvironment of tumours confers upon individual cells in that tumour unique biological properties because this is a very heterogeneous property and because cells in tumours adapt their biology according to their microenvironment they exhibit biological characteristics that are different from each other inside that tumour. So even if they all express the same mutations, they can have very different biological properties, including different long-term regenerative potential such as stemness qualities.

And the microenvironment is a key thing at the moment, are you looking at messaging systems or pathways? How do you think that the microenvironment is actually affecting the activity of the cells that matter, namely the tumour cells.

We think it plays a huge role.

How?

There are two ways that microenvironment influences response to treatment: one is by, again, conferring different biological properties on those cells, so if we take radiation or we take chemotherapy or we take targeted agents, those agents are not going to be equally effective against all the cells in the tumour simply because the microenvironment influences the pathways that are of importance for the response to those agents. So the challenge then is to identify those cells in the tumour that are most resistant to the chemotherapy, to the targeted agents, to the radiation and understand how the microenvironment is influencing those properties. That’s really what we’re trying to go after.

And how is this influence exercised?

The cells sense their microenvironment.

How?

When cells lack oxygen there are several enzymatic systems that are influenced, several cell signalling pathways.

They’re triggered?

That are triggered and these are part of normal adaptation to lack of oxygen. For example, there’s a transcription factor called HIF, it drives many of the biological changes that occur in hypoxic cells, it increases glycolytic capacity, this is why your muscles get sore when they run out of oxygen when you run. It also increases angiogenesis in the tumour, it drives new blood vessel development, it increases red blood cell production so it increases the oxygen carrying capacity of the blood and so on, but it’s only one of several systems that are influenced. For example, our group studies another important pathway that’s influenced by hypoxia called the unfolded protein response. This is because oxygen is necessary for proper protein folding and our cells have a very powerful response when this goes wrong and this influences the biology of the cell, again, in very important ways including the regulation of metabolic properties of the cancer cells that are turning out to be key factors in the phenotype, in the biological behaviour of tumours.

So how are you going to target the microenvironment?

This has been a challenge for many years, in fact, and there have been several different approaches, most of these were focussed on trying to alter the microenvironment itself. What we want to do now is to go after these adaptive pathways themselves, the systems that are responding to the microenvironment to disable those and to make those cells vulnerable to those unique microenvironments that are present in tumours. So, for example, if we can disable the hypoxic response this will result in sensitivity of those cells and they will die under those conditions rather than exhibiting these more malignant properties.

So you’ve given up turning up the hyperbaric oxygen factor?

That was tried, it was, in the early ‘50s.

I’m old enough to remember that, Brad.

But no, I think that going after the biology is the area, at least, that we think has the most potential, is most interesting.

Brad Wouters, good hunting. Thank you.

Thank you very much indeed.