It’s the first day of a New Year and, as is well known, Scottish folk world-wide make a big celebration of yesterday (Hogmanay), New Year’s Day and indeed quite often the next few days for good measure. Even in the far north-west of England as a youngster with more or less black hair (deemed to be important for some reason) I was trundled round the neighbours in one of the rituals — ‘first-footing’, i.e. being the first guest of the new year, despite our family having no Scottish connections that I knew of.
Most such jollifications seem to require mournful dirges accompanying incomprehensible lyrics by Robert Burns. To be fair I should note that Max Bruch and Hector Berlioz, wonderful composers both, saw fit to include a musical reference to ‘Scots Wha Hae’ in the Scottish Fantasy and in the concert overture Rob Roy. Mind you, Berlioz himself described his overture as “long and diffuse” and it was so badly received that he burned the score the night of its premier.
However, there is something else that Scots make quite a fuss about, given half a chance, and here perhaps we can agree they have a point. It’s the number of notable scientists and physicians their country has produced. Wikipedia’s List of Scottish engineers and scientists runs to over 150 names — remarkable for a population that even today is only about five million. The listed luminaries feature some household names: Alexander Graham Bell, James Watt, James Clerk Maxwell, Lord Kelvin and Joseph Lister just to be going on with.
But there’s a slightly unnerving thing about Wikipedia’s List in that, long though it is, there are some serious omissions. I spotted this the other day when I was searching for a bit of background about one of the heroes of this New Year’s story. The first missing star I noted was John Hunter, generally thought to have carried out the first surgical removal of a malignant melanoma (skin cancer) in 1787. Worse still, I found no mention of William Macewen: it was his first successful removal of a brain tumour (in 1879) that makes him directly relevant to our story. He was a truly remarkable figure. Thought of as the ‘Father of neurosurgery’, he was a pioneer in surgery of the brain and other organs. But the really outstanding thing about Sir William Macewen CB., FRS., FRCS, to give him his full handle, was his approach to surgery. Thus, for example, in treating brain tumours he applied his profound knowledge of anatomy to work out from the patient’s symptoms the precise location of the abnormal growth so he knew where to take surgical aim. Amazing!
Very slow progress
Nearly 60 years after Macewen’s pioneering surgery the American composer George Gershwin would have appreciated his genius as treatments had made little progress by the 1930s when Gershwin succumbed to a brain tumour (specifically a glioblastoma multiforme). It took until 1958 for the first useful drug treatment for brain tumours to emerge and until the mid-1970s for radiation therapy come into use. Indeed it was only the introduction of CT scans towards the end of the 20th century that permitted tumour localisation without needing Macewen’s extraordinary gifts.
Something very odd
In parallel with these advances has emerged the evidence for an unexpected feature of brain tumours. You might guess that brain tumours would start in the brain but it turns out that most do nothing of the sort. The vast majority (about 90%) are secondary cancers: that is, they arise when tumour cells spread from another part of the body — commonly breast or lung. In other words most brain tumours are metastases — and they are mighty important. About 24,000 people in the United States discover they have these abnormal growths every year and they cause about 18,000 deaths. The rates are much the same in the UK where deaths from brain and related tumours number just over 5,000.
But also familiar …
Those who follow developments on cancer will know that metastasis is one of the hottest potatoes. Until very recently we had no idea of the molecular goings on that turn a cell in a primary tumour into a wanderer that can leave its site of origin, get into the bloodstream, get out at some other location and there establish a new, secondary colony. The mists are beginning to lift as the wonders of modern biology are applied to this pressing problem.
Step forward one of the main movers and shakers in the field who is the modern hero of today’s piece: David Lyden of the Gale and Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, New York.
So topical is this issue of metastasis that I’m relieved to note that the contributions of the Lyden group have featured regularly in these pages (Keeping Cancer Catatonic, Scattering the Bad Seed and Holiday Reading (4) – Can We Make Resistance Futile). A succinct summary of those contributions would be: (1) cells in primary tumours release ‘messengers’ into the circulation that ‘tag’ metastatic sites before any cells actually leave the tumour, (2) the messengers that do the site-tagging are small sacs — mini cells — called exosomes, and (3) they find specific addresses by carrying protein labels that home in to different organs — we represented that in the form of a tube train map in Lethal ZIP Codes.
In One More Small Step the same team looked closely at exosomes and found that a wide variety of tumour cell types secrete two sizes of exosomes (big and small! — see blog for details!!). Amazingly these sacs carry about 1000 different types of protein — suggesting that they might have powerful effects.
Breaking the barrier
With that in mind Lyden’s group have now turned their attention to how tumour cells find their way to the brain. How do they achieve the feat of crossing the ‘blood-brain barrier’ — the layer of (endothelial) cells that encloses the brain and controls the types of molecules that can move to and from circulating blood — and are exosomes involved? In other words, are they little bags of trouble that play a role in helping most brain tumours to grow?
Answer ‘yes’ of course, or we wouldn’t have spent so long getting up to speed on the subject. Gonçalo Rodrigues, Lyden & Co. set up a brain slice culture system and pre-treated the slices with exosomes from human breast cancer metastatic cells that were known to spread preferentially to different tissues (brain, lung or bone).
Photos of brain slices showing how exosomes help to provide a niche for human breast cancer metastatic cells to invade, attach and grow. These are fluorescence microscopy images: brain blood vessels (vasculature) are red; cancer cells are green (GFP). Left: no pre-treatment; Right: pretreatment with exosomes. White arrowheads show vasculature-associated cancer cells. White bar = 100 microns. From Rodrigues et al. 2019.
The photos show a typical experiment using brain-seeking exosomes. There is a huge increase in the number of green cancer cells attaching to the brain slice as a result of exosome pre-treatment (right) by comparison with no exosome addition (left). Corresponding experiments with exosomes that direct migration to lung or bone show no effect: cancer cell attachment remains low (as in the left hand photo).
How do they do it?
The group took their studies a stage further by looking at the 1000 or so proteins in the exosomes for any that seemed to specify migration to the brain — in other words, to act as addresses of the kind we described in Lethal ZIP Codes. They came up with one in particular: a protein called CEMIP (if you’re interested that stands for ‘cell migration inducing hyaluronidase 1’. It’s an enzyme that chops up long chains of sugars (called hyaluronic acid). These chains form scaffolds to support proteins in various tissues including the brain — and their disruption may play a role in cancer cell movement).
The levels of CEMIP are higher in exosomes that promote brain metastasis but not in those associated with lung or bone metastatic cells. Thus pre-conditioning the brain microenvironment with CEMIP+ exosomes drives invasion. When they are depleted invasion and tumour cell association with the brain vasculature is disrupted. This remarkable new work has revealed how exosomes help wandering tumour cells to storm the blood-brain barrier. Immediately this opens the possibility of isolating exosomes from small samples of blood and screening them for proteins — i.e. using them as a ‘biomarker’ for metastatic cancer targets. But of course the great goal is to be able to interfere with their actions, an intervention that could dramatically cut the incidence of brain tumours. What a triumph that would be!!
We began with a Scottish tradition. Let’s end with another by raising a mental glass to scientists all over the world who, step by perspiring step are inching towards the goal of controlling cancer. Keep it up guys — and back to your benches!!
Rodrigues et al. (2019). Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nature Cell Biology 21, 1403–1412.