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Dr. Steven Griffiths Monthly Column, published in the Times & Transcript
'Tis the Season for Be-ribboning
Tuesday April 21, 2009
Oh sweaty saints and throbbing angels, resplendent in your ribbons and rubber bands. Chances are some of you will be supporting our breast cancer prevention research. But what is it we do? Something in a grey box beyond the keys of your kind hearts?
Not really. Let me put it to you like this.
Not all breast cancers are life threatening. On the other hand, when breast cancer is determined to be dangerous, it may be difficult to use the options we have. How do we sort them out earlier and more accurately?
Our strategy is to first identify common activities shared by all cancers and then use these as reference points to start exploring the unknown.
Think of those “everything jars” we all have filled with loose screws, thumb tacks and other metallic malarkey. Often we have no idea what’s in the jars, what with the layers of pet hair that mysteriously grow and that time we had a party and people thought they were ash trays or places to put peanuts. Or maybe that was squirrels. Let’s say one day we might want to pick out some iron nails to fix a panel on the shed (raccoons using our tools again). So: line up all the jars, get out the magic marker and, after a good huff, code the jars because, hey man, back off: we’re scientists. Next, after several hours of injury and humiliation, we retrieve the super magnet off the bell on Cat’s collar. Time go to work. Hah you jars aren’t so smug now.
“Look large son, cause we be havin’ us some fishing”. We say perhaps to Cat, now uttering threats from the penalty box.
Here come the nails! But what’s this….? Attached to the clump of nails in this jar is our long lost Elmo knuckle dusters. Argggh! In this one…..a MUTANT CYBORG CENTIPEDE! Oh wait. It’s that “silver” charm bracelet the carnival lady sold us, rolled in dust bunnies. Ha! In this jar, we’ve caught one of those little metal neckties that roast chickens wear. What’s that Rod? It’s not from the neck end of the chicken? Ah.
Before too long, and a short marker-induced nap, our fishing has not only landed the nails for our project but also enabled us to itemise what’s in the jars on their labels. This time though with a pencil.
Cancer cells might be likened to our jars: we suspect they may contain interesting stuff, but this it is not immediately obvious. However we do know that there’s a good chance that they all contain elements like the stuff attracted to our magnet. We need a fishing strategy to pull this stuff out.
What might we fish for to determine the personality of a cancer?
Two related things: first, all cancers have to produce an excess of stabilizers called heat shock proteins (HSPs). Second, they all shed waves of cell wall fragments called microvesicles (MVs) into the blood. The two features are related in that, unlike normal cells, cancer cell walls are coated with HSP: the MVs released into the blood end up being covered with them too. MV release serves the cancer cell as a form of communication, at one end of the risk spectrum sharing resources and just scraping by, but at the high risk end stocked with proteins that can turn off immune cells and prepare other parts of the body for colonization. As such HSP-MV overproduction may be common to cancer cells but the stuff that gets dragged out with them is unique and full of useful clinical information. By choosing the right magnet and fishing gear we can separate this stuff out for a good poke around.
How do we land our catch? Let’s talk a bit about HSPs.
When normal cells experience stress (e.g. starvation or over heating) the oily interiors of proteins protrude like hernias and cause them to stick together. Functionally this would be like engine parts fusing. HSPs minimize danger by binding to exposed interiors and reducing stickiness. Cancer cells are under constant stress because they generally live in places they are not supposed to be, with limited nutrients and at high acidity. They also use a varied cast of miscreant proteins that are very unstable. Both regular and cancer proteins are constantly at risk of clumping. Natural selection has thus rewarded cancers that can make a lot of HSPs. The HSPs in turn end up being taken along for the ride to the cell surface and are enriched on MVs that bubble from it. Here’s the “Gotcha!” moment: whatever is bound to HSPs in cancer will include the proteins or microvesicle goody bags that define them, and tell us whether they need immediate attention or are of reduced risk.
What are we going to use for a magnet to catch HSP enriched material? Actually, we eventually do use magnets.
For the past 4 years we have been doing experiments to determine how HSPs and MVs from cancer cells behave in an electric field and then how to catch them using a specially designed protein fragment. Wait: here comes the tie in. The protein fragment bait is attached to microscopic magnetic beads. This means that we can catch the HSP enriched material on the edge of a tube with a super magnet (no chance this time, Cat). Also we are working with friends that have developed proteins called antibodies that stick to specific molecules that always accompany HSPs on the MV surface.
We can wash away the stuff that isn’t attached to the HSPs and MVs on the magnetic beads, bound to the edge of the tube by the magnet, so that it won’t confuse us. Next we break the catch apart and analyze it using a high tech approach called mass spectrometry (see Monster Machines). What with magnets and lasers and robots, it’s a low-tech hi-tech hybrid, by golly.
So far we’ve been practicing this approach on cancer cells grown in the lab. It may be like going for trout at the U-Fish, but boy does it work good. Lab-grown cells are regarded as very different from the ones in the patient-after all they’ve adapted to live in plastic jars. However recently it has been discovered that cancer cells release material into their culture broth that is very similar to that released into a patient’s blood stream: you guessed it- HSP enriched microvesicles. As different as the lab-grown and patient cells are, the communication pathway provided by microvesicle release appears to have been conserved regardless of where they’re growing. For this reason, there’s a very good chance our approach will work in a blood sample.
We hope to start working on real samples in the near future.
So that’s it. One day I hope we may contribute to the sorting of patients quickly and accurately and placing them in appropriate treatment groups. Ultimately our fishing expeditions might improve recurrence-free survival with a side dish of increased quality of life and efficiency in healthcare.
Thank you for your support.
Happy birthday Vicky. I love you.
Stay Frosty
Article as published
http://timestranscript.canadaeast.com/search/article/641710
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