I am currently in Trento, Italy, visiting CoSBI, the Microsoft/University of Trento Centre for Computational and Systems Biology and while preparing my own talk I decided to look for inspiration watching a couple of TED talks talks. I got more than what I bargained for. One that caught my attention was a rather brief one by a very young scientist, Eva Vertes. Her talk was entitled My dreams about the future of medicine but more than a view on the future of medicine the talk was about something quite relevant to me. Her question was why does cancer arise in tissues like the prostate, the breast, the brain, etc but not in the heart or the skeleton muscle?.
She makes other interesting points like assuming that all cancers are the results of stem cells (which would surprise me if it were true) that go rogue as they are reactivated as a result of environmental insult (can’t help liking the word insult as is used by biologists!). She also makes the point that indiscriminate killing of tumour cells is unlikely to be a wise way of curing cancer (which is based on the assumption that stem cells are behind a growing tumour, but this is a statement that also makes sense if you consider that for most therapies, some cancer cells will be more susceptible than others so indiscriminate killing is in effect a selection for resistance).
But back to her interesting question of why is it that we get skin and lung cancer, but not muscle tissue cancer. This is quite relevant as muscle tissues are highly dynamic with a lot of turnover (as muscle tissue is destroyed and repaired during even mild exercise) and are highly vascularised. Her hypothesis (and that was a few years ago) is that evolution might have something to do with that. Precisely because muscle tissue is so highly dynamic and thus, at least theoretically, so good a soil in which to grow a tumour, evolution has made these tissues better able to cope with cancer. Under that assumption, muscles could have plenty of neoplasms, incapable of growing as they are not allowed to co opt the muscle vasculature. Also, due to the dynamism of the tissue, these neoplasms do not last too long. This sounds to me like a reasonable explanation but I am no expert. I wonder if there are other potential answers.
But what about leiomyosarcomas, cardiac sarcomas and rhabdomyosarcomas? And is muscle tissue really more dynamic, as per your definition, than lung, gut or skin epithelia?
I hate to poke a hole in your agrument… but tumours do form in muscle, just not as frequently as in epithelial tissues.
I was thinking that muscle cells in hearts aren’t changed as much as epithelial cells, as far as I remember my anatomy/physiology classes…. Anyway, Darren kind of poked a big hole in the first one though. Although, even if you get cancer in muscle tissues, surely “the other cancers” are more common/prevalent and why would be interesting to know. Maybe something to do with more “touchable” surfaces for environmental factors (i.e. sun and smoke etc)?
The evidence for this idea of an evolutionary pressure that inhibits tumorigenesis in muscle seems to be filtered through the lens of tumor prevalence statistics in adults. Of course hematologic cancers (leukemias and lymphomas) predominate in childhood, but in the category of solid tumors, rhabdomyosarcomas are the most common soft tissue sarcomas in children. IIRC some non-osseous Ewing’s sarcomas also form in muscle. Soft tissue sarcomas increase in prevalence in old age too.
I guess I don’t buy the argument about evolutionary pressures repressing tumorigenesis in highly dynamic tissues. The brain – particularly the cerebellum – is a highly dynamic tissue in young children, and nevertheless, medulloblastoma is the most common childhood CNS tumor. The sites and cells-of-origin for the most common cancers change in prevalence throughout the human lifespan, and I think the model presented ignores that.
Hope your talk goes well, David!
The idea of environmental insult is still a valid one, in my opinion. And simple cell division is taking a major risk of introducing an unrepaired mutation right there. So exposed epithelia, both inside and outside (eg. skin, lung, gut), are taking more hits than other tissues during that vulnerable time. However, such insults can occur at any moment, and are not always linked to cell division per se.
There has been a similar argument based on epidemiology that the last sites of neural tube closure are those that are most vulnerable to developing neural tube defects. It was a nice idea and still has a lot of traction in many quarters, but observation in human embryos is just not that consistent with the prevalence of different sorts of NTDs.
What is difficult about rebutting both arguments is that there is probably a grain of truth in each. But if biology has taught us anything, it is that things may be elegant, but they are not always so simple. If you kill muscle or brain cells in the adult, they stay dead. There are so-called satellite cells in the muscle, and some rare stem cells in parts of the brain, that can be called into play under the right circumstances. This is a fascinating subject of research. It is probably much less frequent that a carcinogenic mutation occurs in one of these usually quiescent, and rare, lineage-specified brain/muscle stem cells in the adult, than in the oft-solicited stem cells of the epithelia mentioned above. And cancer can occur in any cell to my knowledge, if it gets induced to enter the cell cycle again. While all cancer cells are of course not stem cells, some of them may share important properties with them (and use the same gene products) and for all intents and purposes can be called “cancer stem cells”.
Can I get invited to give a talk at TED now?
Hi David,
enjoy Trento, such a nice part of Italy.
If muscle did not develop cancer at all, then of course they would have been a terrific area of scientific investigation, since they would have thrown an exception, right in Homo Sapiens.
On a related note, I was rather intrigued by the thought that sharks don’t ever get cancers, an evidence (or rather, a lack of evidence) that may have possibly been linked to their stange immune system. Too bad that was a myth.
Try to make a trip to Lake Garda (great windsurfing or mountain biking there) or to the Mountains, if you have time. Ciao!
Interesting post, I hope you have a pleasant conference!
Perhaps the key point here is what you mean by “dynamic”. Muscle tissue has very little turnover of cells, but a rather large turnover of intracellular components. Epithelial tissues, on the other hand, typically have a quite rapid cycle of cell death and renewal that is driven by stem cells. In terms of cell proliferation, muscle cells are arguably among the least dynamic cells in the body.
This is related to the complex structure of muscle cells, which are huge (up to several cm long) and multinucleated. They are formed by fusion of mononucleated myoblasts, and pretty much incapable of any further cell division. Tumors from muscle tissue are probably formed mainly from the mononucleated progenitor cells. These are of course far more abundant in childhood, when the incidence of muscle sarcomas is also highest (as Kristi has already pointed out).
The argument about evolution having given the most dynamic tissues some sort of extra protection against tumorigenesis is perhaps more relevant to other tissues, in particular the epithelium of the small intestine, where cancers are surprisingly rare in spite of the fast turnover of the epithelial cells. But all of the most common tumors arise in highly dynamic tissues (breast, prostate, colon, skin, bone marrow), so I don’t really see the where this line of reasoning becomes useful (although I haven’t seen the actual TED talk and should probably reserve my opinion).
Thank you all for this online conversation. This is the sort of thing that I wanted to initiate when I wrote this post.
The idea that tumours do not start from muscle tissue is only my interpretation of Eva’s talk. Is not that much that I had anything to add to her idea but I found intriguing (as she did) that some tissues do not develop (often) cancer even if they are very dynamic and highly vascularised. Being accurate, Eva’s talk was about skeletal muscle which represent a significant amount of tissue. These type of tissue is subject to loads of wear and tear which means that the tissue has to be constantly repaired. This is not necessarily the same than cell death so the opportunities for tumour initiation are probably not as high as tissues with loads of cell divison and death (as Gustav pointed out). Still, they are dynamic tissues in constant change and microenvironmental transformations are known to correlate with cancer initiation. So even if I got it wrong (not if, I did get it wrong) and there are skeletal muscle cancers I still wonder 1) whether they are statistically more, less or as significant as those in epithelial tissues given the amount of muscle tissue and the rarity of muscle-related cancers and 2) assuming that this is the case, whether evolution has selected for muscle tissues to be better at warding off cancers resulting from environmental change (although I suspect that Kristi doesn’t buy this).
Massimo: Trento is definitely a beautiful town and the mountains around here looks very tempting but unfortunately tomorrow I will be visiting Malpensa instead :(
Heather: I would love to see you talking at TED, I only wish I could issue the invitations!
David, it’s fun to toss around ideas like this. Not only do we not all have the same vocabulary, we definitely don’t have the same baggage of underlying knowledge. My impression of cancer (as a developmental biologist) was as the removal of the growth inhibition of a cell in a differentiated tissue, and acquisition of an invasive, sometimes mobile phenotype. (Thereby reverting, in some respects, to an inappropriately embryological state.)
I don’t tend to think of cancer cells as internal traitors that are damaging to the body but because of their insider information are able to get around the immune system. Or as something against which an organism with better defenses would have a selective and reproductive advantage. So the different backgrounds of the participants in the thread are very interesting. I still remain to be convinced, though, of the evolutionary argument. Rather, like for birth defects, it is enlightening to take the perspective that it is rather wonderful things don’t go wrong more often – and in that respect, Gustav’s remark about the ability of rapidly proliferating tissues to usually do so faithfully, without carcinogenesis, bears more weight.
Hi David, I read the post and started jumping, but when I got to the comments found the main points that bugged me had been covered by the biological contingent in your audience. As Heather notes this is one of the joys of posts on the edges of our comfort zones.
The incidence of epithelial tumors (carcinomas) versus stromal tumors (sarcomas) varies. In humans age is a factor – the various sarcomas are generally more common in children versus adults, while carcinomas become more common with age. Noted above, in previous comments. The incidence of these lesions also varies with species. Many experimental animals, such as mice, naturally get far more sarcomas than humans and relatively fewer (naturally occurring) carcinomas. Some of this might be genetic, for example Labrador dogs apparently have a relatively high incidence of osteosarcoma, compared to other strains. Chromosomal structure might also play a role. Work from DePinho’s group suggests that telomere length might play a role in suppressing the incidence of carcinomas, thus mice with their long telomeres get less carcinomas than humans with their relatively short ones.
In common with views expressed above I would also expect that environmental factors play a role, and am comfortable with the idea that epithelial cells acquire hits with time. In some tissues (skin, gut, lung, bladder, as examples) this seems obvious, however other important cancers including breast and prostate derive from tissues that could be thought of as relatively protected from insults and yet still undergo common transformations. I guess this leaves open the door for hormones and environmental hormonal mimics, the bane of my existence! It also, happily, leaves open possibilities for microenvironmental regulation of carcinogenesis.
Have a good trip.
Hi Heather, thanks again for your comment. I do share your view that tumour cell are not that much agents that are trying to get us as much as cells that stop responding to homeostatic environmental signals for one reason (they fail to sense them) or the other (the signals fail to reach the otherwise normal cell). But as a tumor progresses the tumour cells acquire phenotypic traits that make them increasingly different from the unaffected cells in the tissue.
The evolutionary argument affects both initiation and progression. As for the first, if our development programmes have been produced and shaped by Darwinian evolution then it is unlikely to be bullet-proof (not literally). Also it is unlikely to withstand all perturbations equally well, with an increasing likelihood that the more common perturbations will be better handled than the less frequent ones. Thus, under that view, if putting stress on a tissue like skeletal muscle, happens often enough it is conceivable that evolution would have made the responsabile section of the developmental programme better capable of handling that situation.
@David, I don’t agree with your line of thinking on Darwinian selection. Most tumours (especially epithelial ones) occur in older people, in fact age is the #1 risk factor for cancer. Getting breast or prostate cancer at the age of 50-something is not likely to have a major effect on reproductive fitness so the selective pressure against these events is relatively low. No doubt environmental exposure is important, but I tend to agree that the very low levels of cell division in adult muscle (compared with most epithelia) is a major factor. Muscle cells are dynamic from the perspective of protein turnover and metabolism but almost quiescent in terms of mitosis (as covered in comments above)
@Simon, it’s interesting that very few known human tumour suppressor gene mutations produce the same spectrum of tumours in mice as they do in humans. For example, p53 (which interestingly also causes a highly penetrant neural tube closure defect in mutant female mice)
Darren, I should let David speak for himself but my understanding is that he is more interested in the idea of quasi Darwinian selection acting on the cell populations in the growing tumor rather than the effects on the fitness and reproductive success of the host. So it gets to be about how the tumor evolves.
Your remark re the tumors that specific mutations give rise to in mice is spot on, and really validates the need to perform work on human cells, tissues and organs in vivo (not to promote a personal hobby horse or anything).
As a personal chat item: from your profile I realize we must know a number of people in common – I have friends at both BCCA and the Garvan.
Simon, fair point… it’s hard to get into that discussion without invoking the whole notion of “cancer stem cells”. I don’t think I have the energy for that this morning ;)
I was at the Garvan for a few years, who do you know there? Small world hey?
Simon, you presented my view rather well. The evolutionary dynamics I was thinking of is the one at the scale of tumour progression with cell with different phenotypes and traits competing for resources and space. The role of stem cells in cancer initiation is quite intriguing but not sure we are even close to know enough to start hypothetising much about it. Still, would like to read what Darren has to say about it.