IMPAKT Breast Cancer Conference 2013

Extracellular matrix proteins of stem cell niches promote breast cancer metastasis

Dr Thordur Oskarsson - HI-STEM, Heidelberg, Germany

Thordur, you’ve been telling the meeting here in Brussels about niches where metastases can take a foothold in the body. Can you tell me about these extracellular matrix proteins you’ve been looking at? First of all, what did you do in the studies you’ve been undertaking?

What we have been looking at are the role of the extracellular matrix molecules in metastatic niches. We believe that the extracellular matrix plays an important role in the niche.

What is a metastatic niche?

A metastatic niche is basically the microenvironment that can promote survival of cancer cells and their metastatic outgrowth at distant sites.

Basically the body is set up to reject cancer cells because cancer self is not self and therefore normally the microenvironment is hostile. So these niches are different, is that it?

Exactly. The cancer cells that go out of the primary tumour and end up in distant organs where they don’t belong and is a foreign environment for them, they face a significant resistance and they have a way to manipulate the microenvironment in their own favour to grow out and form metastases.

You’ve been looking at these niches in model systems, what did you have to do?

What we do is to use knockdown, so helping RNA to knock down these genes and analyse their functional role in metastatic progression using the xenografts mouse models.

So in animal models you’ve been able to do what?

We reduced the expression of these molecules and we see a significant reduction in the metastatic outgrowth in lungs and in the bone.

So talk me through this, the cancer cells reach the place that’s going to be a niche, what actually happens? The expression is changed there, the hostile expression, is that it?

Yes. This might be dependent on the abilities of individual cancer cells because there’s a significant heterogeneity within a tumour and between the cancer cells. So some cancer cells may be more capable than others to promote the favourable microenvironment at the distant sites. Others may actually bring their own niche component by expressing these extracellular matrix molecules themselves, so bringing their own niche component to a distant site. So they will basically be gaining a significant advantage and hit the ground running, as we say.

So there are molecules in the extracellular matrix which can be switched off, their ability to fight this not-self molecule is switched off by the cancer.

These extracellular matrix molecules that we are interested in are molecules which are normally not expressed highly in the healthy individual. They are expressed during embryo development but highly restricted in adult tissue. However, during tissue remodelling and stress response like wound healing and inflammation, they are up-regulated significantly and in addition they are also up-regulated significantly in cancer. So we believe that they are promoting signalling pathways that are important for embryo development and stem cell characteristics in the cancer cells.

Now theoretically, based on what you’ve discovered in the mouse xenografts, what might conceivably be happening in breast cancer? For instance when it metastasises to bone what would happen to make that possible?

Basically because of this resistance of the environment, when a cancer cell, for example from the breast, ends up in the bone or in the lung they have to resist this significant hostile environment, let’s say. What these molecules do is to promote the viability and fitness of the cancer cells by stimulating signalling pathways that are involved in stem cell features. Because of this they are able to self-renew, similar to what stem cells do, and grow out into metastasis.

And how might that translate into treatments that could switch off this process and prevent metastasis?

I think it’s very important to study carefully and to dissect both the interaction of the extracellular matrix with the cells as well as the signalling pathways that these extracellular matrix molecules promote to be able to identify putative drug targets or putative targets that we could inhibit. So I think it’s important, we don’t know which one would be the most feasible target but we need to know the whole pathway to be able to identify the right one.

So you’re getting somewhere close to looking at individual, for instance organ-specific, sites of metastasis; what about more disseminated disease – have you got any way towards understanding that?

What we have seen, actually, by looking at cancer cells isolated from plural fluids, which is the fluid that accumulates in the lungs of patients with systemic disease, we have seen that these cancer cells, they express high levels of these extracellular matrix molecules. And they would represent the most aggressive cancer cells which does suggest that the most aggressive cancer cells might express their own niche components to viability in any organs basically.

Are you saying that the proteins in the extracellular matrix are actually responsible for helping these niches to develop?

Yes, they are definitely a significant component of the niche and they play a big role in promoting signalling pathways, for sure.

What do you think doctors might make of this and how might some of this knowledge transfer into clinical practice?

I think it’s very early to say and, like I mentioned earlier, we need to dissect these pathways and dissect the function of the extracellular matrix molecules to be able to identify the most feasible drug targets.

For example, bisphosphonates have been found to have quite an influence on reducing metastasis to bones in some situations, breast cancer for instance. That suggests that maybe there’s something happening here to dampen down that rate of establishment of the niches.

Yes, for sure, since it significantly reduces the resorption of the bone which is caused by the vicious cycle in bone metastasis. Yes, that would definitely be an indication that targeting the niche in addition to targeting the cancer cells would be important for curative therapy.

Are there any other potential ways of targeting those niches, do you think, coming up?

To my knowledge I don’t know at the moment, no.

So what would you like doctors to take home from these messages you’re giving out today?

Basically it underscores the importance of targeting both the cancer cells as well as the microenvironment to get the most effective therapy.

And the take home message of all this endeavour? Do you see it going in other directions soon too?

We are currently exploring different extracellular matrix molecules. We have been studying a molecule called tenascin-C and we are currently exploring different extracellular matrix molecules which are of the same family. We believe that they may play a significant role similar to tenascin that we have been studying so far.

There’s a lot of signalling going on in the body, though, how significant are these niches and the whole modification of the environment compared to other factors which could help the metastatic process? Is it a big part or a small part?

I would think it would be a big part and particularly because they promote signalling pathways which are normally not activated in adult cells or, let’s say, differentiated adult cells. So these are signalling pathways which are activated in stem cells and embryonic cells. So they’re important for development and when they are switched on the cancer cells gain significant advantage for self-renewal abilities and metastatic output, basically.

And how long do you think we might have to wait for some practical messages to come?

That is very tough to say. This is currently at a very early stage but I think it’s very exciting. However, I think that there is going to be a significant time, yes.

Thordur, thank you for letting us in on all of this fascinating work.

Thank you very much.