h a l f b a k e r yQuis custodiet the custard?
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Metastasis of solid cancers is encouraged by the release of collagenase by the cells in order to break down the basal lamina and enter the bloodstream. Although cancer does spread in other ways, this is one which can be dealt with by the immune system. Take B cells and expose them to the appropriate
collagenase, clone them and reintroduce them. Since they're able to leave the bloodstream themselves, they might be able to find tumour cells and inhibit their enzymes, slowing the spread of cancer.
One of my worries with this is the physiological function of collagenase, since i imagine this approach could lead to osteoporosis or slow the proliferation of fibroblasts.
Just a thought: probably bollocks.
Matrix metalloproteinases
http://en.wikipedia...x_metalloproteinase
[bungston, Jan 26 2009]
Use local TIMPS
http://www.nature.c...8/abs/1201774a.html
Inhibiting MMPs locally may help [leinypoo13, Jan 26 2009]
[link]
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Cool man --- I likes them big words... |
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--- Metastasis: spreading |
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--- Collagenase: helps hydroysis (add water) |
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--- Basal lamina: a bit of a cell (in this case I suspect containing cancerous agent) |
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Exactly why will these modified B cells not inhibit normal cell activity? |
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[madness]; sp. hydrolysis? (Either that, or I'm completely lost!) |
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OK. One way cancer cells spread is by dissolving a layer between them and the blood with a chemical. If you got lots of cells to make something which stuck to the molecules of that chemical and stopped it working, then put it into the body, they could stop cancer cells from doing that. But you're right, [madness], there would probably be a problem because scar tissue and the bone cells need that chemical to work properly. Also, it wouldn't help with the likes of leukæmia, tumours which secrete hormones, problems caused by compression or various other things. |
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It is a good idea. It would be easier to block an enzyme with a small molecule than to Tom Sawyer a bunch of B cells to try to learn how to block it. But despite being plausible, this approach did not help people - see link. |
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I agree with the likely problems caused by widespread and
probably irreversible inhibition of collagenase. Also two
other problems: |
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1) You won't easily elicit a B-cell response against
collagenase - it's part of self. B-cells already encounter it
naturally. You'd be better treating with a humanized
rodent monoclonal or phage antibody. |
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2) Aside from the problem of blocking the good functions
of collagenase, you'd also probably start a massive
autoimmune response if you could get B-cells to recognize
collagenase. |
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Right, thanks for all that, that's bloody brilliant. So, and this is a bit off-topic of course, does that mean there could be a link between the destruction of alpha-1 antitrypsin in the lungs by tobacco smoke and the increased risk of lung cancer? I'm thinking that either the collagenase is inhibited by the antitrypsin itself or there's some kind of pathway in common between the interference of tobacco smoke with the antitrypsin and some other collagenase inhibitor. Does anyone happen to know anything about that? I've thought in the past that one reason for tobacco being carcinogenic is the interference with the mucociliary escalator making it harder to clear the lungs of other carcinogens, but that was just a guess. I do realise that the likes of benzopyrene doesn't exactly help, but i would expect it to be multifactorial. |
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Anyway, back to the point. I did think of an antibody without the B cell, but i couldn't think of an efficient method of delivery. I liked the idea of using a B cell because i see it as basically a biological machine which hunts down nasties and zonks them. If it was just an antibody, how well is it going to be able to bind to smaller metastases? Would it not then just be a case of applying it to known tumours and missing smaller ones? On the other hand, maybe it needs to be aimed in that way to avoid screwing with the physiological actions of the collagenase. |
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On the other hand, how feasible would it be to modify a tumour cell to produce a collegenase inhibitor which would act locally? In that case, you would be producing relatively benign tumour cells which wouldn't cross the basal lamina themselves (ineffective collagenase) but which would stop local collagenase from working. So, you could stick those tumour cells into the malignant tumour and they might inhibit the metastasis, while further away, the collagenase inhibitor is dilute enough not to interfere. |
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Hmm. I should declare an interest since (a) I smoke and
enjoy it and (b) one of my research projects is on lung
cancer (genomics thereof). Not sure about antitrypsin
thing. For delivering antibodies, there isn't a great
delivery system; only option so far is to humanize the
antibody (to make it look natural to the immune system,
otherwise you make anti-antibody antibodies) and then
inject it, as with Humira, Herceptin etc. |
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As for engineering a benign tumour cell to produce a local
collagenase inhibitor - difficult; and you'd have to do it for
each patient, starting with their own cells. However, I do
like the idea of fighting fire with fire. |
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One thing to bear in mind (just as a background useful
thought) is that cancer is an evolving population of cells.
If you start thinking in those terms, it gives you a nice
handle on why so many treatments fail. There's a good
book called "Cancer: the evolutionary legacy" which
addresses this. |
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I have in fact been looking at cancer in those terms recently, though how applicable it is to what i do for a living is another question. On the other hand, i'm hardly about to pay for a seminar which tells me what a good idea bloodletting is, so the term "waste of time" is relative. Thanks for the book recommendation, it sounds fascinating and i'll certainly be looking into that. Concerning the use of the patient's own cells, what about contaminated cell lines? Are there not cell lines out there which will take over if left to themselves? Would they do the same thing in vivo and if so, would the immune reaction be too much to handle? Could the antigens on the cell surface be changed in a similar way to the blood group change thing? |
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Yes, there are some very aggressive cell lines (such as
HeLa) which will take over other cultures if they get in.
However, they aren't fighting an immune system in
culture. In a person, they'd probably be wiped out in no
time flat (or, if they didn't, it would be more worrying). |
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What you're after is a sort of equivalent of a "Type O" cell
line, that have no distinguishing surface features and
would be left alone by the recipient's immune system.
However, that only works for red blood cells because they
have a very simple surface (and, in the case of O cells,
none of the surface antigens that distinguish one blood
type from another). For "real" cells, I don't think it could
be done - they have lots of junk on their surface, and the
details of the junk differ from person to person. But I may
be wrong - you might be able to engineer a "universally
tolerated" nucleated cell. |
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Hi BeanAngel! How ar.. eeehh... oh sorry, 19thly, I'll reread! |
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I sorta liked the last sentence. |
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Yes, i thought myself that it sounds like one of [beanangel]'s ideas. |
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How about a relatively small number of cell lines with similar HLA antigens and maybe some immunosuppressive drugs at the same time? |
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Well, posssssssibly. But you're still up against the other
problems... |
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It would violate the Hippocratic Oath, but provided the other problems weren't lethal, and i know that's a big "but", maybe they could be dealt with later. Once the crisis of the initial tumour was over, the new tumour cells could be removed? I dunno, i've been lugging tree trunks about all day and i'm knackered. |
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I think the problem is that inhibiting collagenase is
probably only going to delay metastasis, so it's like holding
back the waves. I presume (though I'm not sure) that
collagenase is secreted; this means that you won't be
attacking the cancer cells themselves, I guess. |
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On the other hand, you can pick holes in most cancer
treatments, and many of them will work to a degree.
What you need are lots of approaches, probably in parallel,
because you're trying to kill a moving target. Each round
of treatment is likely to leave a small number of surviving
cells which have evolved a way around that particular
roadblock. So, the more the merrier. |
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There are certain conditions which are described as things one is more likely to die with than of, and delay is, well, not fine, but better than nothing if it means something else gets you first. |
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Very true. I'm just not sure that holding back metastasis
with a collagenase screwer-upper would give you a lot of
extra time. On the
other hand, I'm not a "proper" cancer researcher, and
certainly not on the clinical side, so who knows. |
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