AACR 2016

Metastasis initiation mediated by Thrombospondin 2

Dr Ilaria Malanchi - Crick Institute, London, UK

Mainly the effort of my lab has to do with understanding the distant tissue response, the metastatic response to the cancer cell when the cancer cells want to grow in a distant tissue. So the tissues require to change in order for the cancer cell to adapt to that new environment and this response is fundamental for the metastatic spread.

Recently we have tried to understand what do they have, the cancer cells which are successful, more than the others in triggering this cross-talk with the distant tissue. We identified a factor which only the more metastatic cells have which is capable of triggering a faster stromal response. So this changed tissue is called metastatic niche so those cells are more capable then to trigger this metastatic niche. Importantly, this thrombospondin 2 also represented a potential target for blocking this fundamental cross-talk.

Another study which we have made which is very interesting has to do with the fact that a tumour growing in a primary tissue triggers a systemic response in the body. So neutrophils from the bone marrow are increased, they are released in the blood and then they spread systemically into the tissue. This tissue will have now an accumulation of neutrophils which happens only in the presence of a primary tumour. So effectively when a cancer cell infiltrates that tissue we’ll find an increased number of neutrophils compared to someone that doesn’t have the disease. We discovered that neutrophils then engage in apparent cross-talk with the cancer cell, release a factor which is called  leukotriene, it’s an inflammatory factor, which boosts and selectively helps the more metastatic cancer cells to initially start proliferating into the new tissue.

We tried to use an anti-inflammatory which is normally used in asthma to block the release and the production of this inflammatory factor from the neutrophils and these effectively inhibit and reduce metastatic spread into the lung. This is in the model of breast cancer metastasis to the lung.

Can you describe the anti-inflammatory factor in more detail?

This is a lipid, they are secreted by neutrophils, mainly leucocytes, and they are called leukotriene. They signal via receptors which are normally present on the immune cell, so there are the type 1 receptors which are spread on the immune cell but the cancer cells have a type 2 receptor which are still efficient in triggering a response in proliferation, a different type of response which would occur in cancer cells or inflammatory cells. Normally these signals are used to co-ordinate an inflammatory reaction so they are normally essential for co-ordinating the reaction. But in the context of tumours they can turn in favour of the tumour.

Does this increase risk of compromising another infection?

Not really because they only take away one component and it doesn’t really compromise an overall imfection. It’s normally used for inflammatory disease to reduce acute response.

Does this increase risk of compromising another infection?

In asthma, for instance, in the context of the lung that’s important.

Coming back to the first thing you’re working on, you mentioned there was a factor there, I would like to hear more about that.

Can you tell me about thrombospondin 2?

That one is more complicated because we don’t really have a strategy to block it. We have characterised it as a new factor which triggers a stromal response into the tissue and, of course, stroma in terms of fibroblasts and activated fibroblasts are also an important component within the metastatic niche. They normally appear again in the event of wound healing, so tissue injury responses, and again they’re providing a lot of good signalling for the cancer cell to block. But we don’t know yet how thrombospondin 2 is effectively… We know it’s mediating this activation by binding [?? 4:44] but we don’t have a strategy to block that interaction at the moment, so to turn it into a therapeutic assay we don’t really have the tool at the moment but we’re looking for it.

How do you expect this to change future practice?

The idea is that this, per se, will not block a cancer cell. So it will reduce the efficiency of the metastasis, for example, and will make a cancer cell more vulnerable to targeted therapy. So all the strategies to target the tumour back environment would be ideally used to weaken the cancer cell, to reduce relapses and to reduce resistance to the targeted therapy which effectively targets the cancer cell. So with all these tests that we are doing in vivo using mouse models we are targeting only the microenvironment and we already see a reduction in metastasis. This augers well for a use of this strategy in combination with standard therapy.

What is your take home message?

The conclusion is exactly what I was pointing at at the end, it’s to make efforts to target this incredibly important response of the tissue and the entire body to the cancer disease. Because a cancer cell is not self-sufficient and to succeed and grow within a tissue, within a body, it requires co-ordination of a lot of other signalling which comes from the body. So blocking that will solve many problems in terms of relapses and resistance to the target therapy which targets directly the cancer cell.