Movement and growth of cells throughout the leptomeningeal space

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Published: 11 May 2018
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Dr Adrienne Boire - Memorial Sloan Kettering Cancer Centre , New York, USA

Dr Boire talks to ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about potential routes for cancer cell, and also immune cell, entry into the leptomeningeal space.

She also studied the gene expression of the cancer cells which managed to grow in this nutrient sparse environment, and what unique features result from those genes.

I was speaking about the leptomeningeal space predominantly. The leptomeninges are another anatomic compartment in the central nervous system that is often neglected. The brain and the spine’s parenchyma is really served and protected by the blood-brain barrier and the cerebrospinal fluid, its composition is governed by the blood CSF barrier which is formed by the choroid plexus.

So I discussed potential routes for cancer cell entry into the leptomeningeal space as well as immune cell entry into this space. Then I discussed some novel findings, both from myself and others, that might explain how immune cells might exit the space and how we might actually therapeutically intervene in this area.

My work really focuses on cancer within the leptomeningeal space and in studying cancer in this space one of the questions that we really wanted to ask was how is it that cancer lives in this space because the cerebrospinal fluid is actually a very nutritionally sparse material. So there’s not very much protein, there’s not much glucose nor are there many growth factors or metabolic intermediates to really sustain cancer cell growth and yet the cells grow in this space. So through iterative in vivo selection of some mouse models I was able to create some subpopulations of cancer cells that grow within the leptomeningeal space. Looking at gene expression profiling I was able to find that the cancer cells that have the capacity to live within this environment secrete a factor called complement C3. Doing some mechanistic work in both in vitro and in vivo and from human samples we were able to find that the cancer cells secreting C3 that a split product from this C3a leads to activation of the C3a receptor on the choroid plexus and that this leads to opening of the blood CSF barrier and entry of some plasma contents into the CSF. This alters the composition of the cerebrospinal fluid such that it’s able to sustain cancer cell growth.

In this way the cancer cell broaches the blood-CSF barrier and creates a leaky, almost pseudo-oedematous situation for itself in that this is really one of the ways in which cancer is able to circumvent the natural anatomic barriers.

What could these findings lead to?

The cancer cell C3, the way that it signals to the choroid plexus is through the choroid plexus’ C3a receptor and this is a G protein-coupled receptor so it’s a very druggable target. In fact, there are C3a receptor agonists and antagonists that have been previously generated that have been used in the context of asthma. So although they were not useful for asthma perhaps they might be useful in this context.

Is there a need to improve training and the number of medical professionals in this field?

In the United States we already have a system in place to train neuro-oncologists. So the path in the United States is really after residency in neurology or in medical oncology then you can do another level of subspecialty training in neuro-oncology and that’s typically about two years in length. After that there’s a Board examination and then you become a neuro-oncologist.

I adore my job; it’s very personality dependent. It’s very difficult work, our patients are extraordinarily ill, but there’s quite a lot of room for improvement if you’re an optimist, as I am, and there’s quite a lot of research. It’s a wonderful interface to exist in, actually, in this place where you’re able to see patients, enrol them in clinical trials and really feel that you’re contributing both to the patient in front of you, to the health and welfare of the person that you’re taking care of but also contribute to the larger project of helping lots of other patients.