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Slow down metastasis with anti-collagenase B cells

Transfuse B cells with immunoglobulins against collagenase to counteract tumour cells
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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.

nineteenthly, Jan 26 2009

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]






       Cool man --- I likes them big words...   

       --- Metastasis: spreading   

       --- Collagenase: helps hydroysis (add water)   

       --- Basal lamina: a bit of a cell (in this case I suspect containing cancerous agent)   

       Exactly why will these modified B cells not inhibit normal cell activity?
madness, Jan 26 2009
  

       [madness]; sp. hydrolysis? (Either that, or I'm completely lost!)
pertinax, Jan 26 2009
  

       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.   

       That's what i'm saying.
nineteenthly, Jan 26 2009
  

       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.
bungston, Jan 26 2009
  

       I agree with the likely problems caused by widespread and probably irreversible inhibition of collagenase. Also two other problems:   

       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.   

       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.
MaxwellBuchanan, Jan 26 2009
  

       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.   

       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.   

       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.
nineteenthly, Jan 26 2009
  

       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.   

       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.   

       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.
MaxwellBuchanan, Jan 26 2009
  

       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?
nineteenthly, Jan 26 2009
  

       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).   

       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.
MaxwellBuchanan, Jan 26 2009
  

       Hi BeanAngel! How ar.. eeehh... oh sorry, 19thly, I'll reread!
daseva, Jan 26 2009
  

       I sorta liked the last sentence.
neelandan, Jan 27 2009
  

       Yes, i thought myself that it sounds like one of [beanangel]'s ideas.   

       How about a relatively small number of cell lines with similar HLA antigens and maybe some immunosuppressive drugs at the same time?
nineteenthly, Jan 27 2009
  

       Well, posssssssibly. But you're still up against the other problems...
MaxwellBuchanan, Jan 27 2009
  

       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.
nineteenthly, Jan 27 2009
  

       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.   

       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.
MaxwellBuchanan, Jan 27 2009
  

       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.
nineteenthly, Jan 27 2009
  

       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.
MaxwellBuchanan, Jan 27 2009
  
      
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