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comment by mk
mk  ·  1918 days ago  ·  link  ·    ·  parent  ·  post: Cancer cells can ‘infect’ normal neighbours  ·  

That's one of those kinds of questions that I think can only be answered experimentally. The cascade of miRNA effects could very well affect telomorase, and beyond that, most of the contents of the exosomes remain unknown. In fact, I've seen a few reports that suggest that miRNAs only constitute about 1% of the total RNAs in the exosomes (This has led me to my current investigations into the abundance of other short non-coding RNAs found within). Also, who knows what other mechanisms that we are completely blind to that might be involved, like miRNAs such a short time ago.

Personally, I do my best to take definitions like the 'hallmarks of cancer' with a grain of salt, as definitions can obscure the important assumptions that underpin them, or they might lead you down the garden path. Of course, such definitions are useful for discussion but if you focus upon them too much, you find yourself having philosophical or taxonomic discussions, or start saying silly things like 'junk DNA'. My approach is to just wonder within the realm of what is physically possible, and if something seems physically possible, then test whether or not it is so.

One thought that I have been having regarding these findings, is whether or not all metastasis is actually cellular. Is it possible that metastatic tumors could originate via exosomal influence? After a certain exosome load, might the body start spontaneously sprouting tumor? Probably much more likely the exosome influence creates fertile ground for metastatic cells, but at this point we really can't exclude the possibility. That said, I am not sure the extent to which met tumors have been exhaustively linked to the parent tumors. I work in glioma, and they are rarely metastatic.

My guess is that after a certain point, these converted cells could produce progeny that fit the bill, especially once they start acquiring chromosomal aberrations. I actually had an astrocytic cell line turn very tumorigenic on me after a transfection with one protein. I've since performed a miRNA array on the parent and the tumor, in addition to three other rat gliomas. Interestingly, the astrocytes that turned malignant have a miRNA fingerprint that is much closer to the three other tumor lines than it is to the parent cells. If you consider the hundreds, if not thousands, of targets for those miRNAs, that's pretty striking. But then again, Dolly the sheep was a mammary gland cell. If epigenetic influence can make a mammary nucleus build a sheep, then I would imagine that non-tumorigenic cells can be epigenetically coerced into the real deal.

thundara  ·  1918 days ago  ·  link  ·  

Reply appreciated. Thank you for giving me a bit to stew on. I remember reading about early fights in favor of oncogenes as the source of cancer. In a way, this is cancer research come full circle back to non-genetic sources of tumors. Think exosome-budding-protein could be the next big cancer blocking target?

mk  ·  1918 days ago  ·  link  ·  

Thanks. I have my doubts that it'll be a protein, but who knows. Prions are crazy. Maybe exosomes can carry something like that. There was a recent paper showing that exosomes are enriched in transcription factors. I suppose there could be a protein linchpin in there. From my experience, there are a number of avenues to tumor, and a number of ways to potentiate each path. For some tumors, if you find an early catalyst, you are all set. But, for some like glioblastoma, there are a number of paths to a similar malignancy, and any treatment will only hit a subset. What's worse, is that they are so unstable, they can become independent of the pathway that underpinned their malignancy. Unfortunately, for those tumors, the closer you get to a treatment that includes them all, the more likely you are to have something systemically deleterious.

I have the half-baked notion that exosomes could be an appropriated viral mechanism from long ago, not unlike mitochondria. But, it really doesn't matter the origins; viruses demonstrate an efficient way to broadcast a genetic message, there's no reason why cells couldn't convergently evolve onto similar behavior. What I am saying, is that perhaps the body 'infects itself' all the time as a matter of course. It would be an interesting way to keep such a large system in sync. This 'infection' machinery going awry might be an overlooked component of cancer. Of course, this might not be the case, or maybe it's only true in some contexts, but IMHO it's worth thinking on. We draw distinctions between cells/tissues/organs/etc. But a nucleotide has no idea what it is part of, or how it is put to use. Do miRNAs serve cells, or tissues, or organs? It will serve any of them to the extent that it performs a useful function, and thus, is probably serving them all.

For my part, I am currently looking into if something makes a cell 'listen' to the miRNAs in exosomes, or alternately, if they might be inclined to 'ignore' them. I have a candidate, and I have the miRNA transfer model that we previously used.

thundara  ·  1918 days ago  ·  link  ·  

    But, for some like glioblastoma, there are a number of paths to a similar malignancy, and any treatment will only hit a subset.

Yeah, I was talking to a proteomics guy about variance in protein activity across a tumor. He was saying that if you took samples from far apart on a tumor, you saw almost no correlation in activity. In fact, if you took samples from right next to each other on a tumor, you saw almost no correlation in activity.

Cancer's weird, miRNAs are weird, and now I'm going to throw "exosomes" are weird into that bucket, too. Still, food for thought in all of the above.