Knowing my fascination with body size variation among organisms , Peter sent a link along for a new paper, “Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox.” Included in the email was a gentle prodding to post on this unique paper.
Peto’s paradox is that cancer is fundamentally different across mammals. If all mammalian cells have an equal probability of developing a mutation leading to cancer, all else being equal, then larger sized organisms with more cells should have a higher incidence of cancer. Equally, because larger organisms are longer lived then the probability also increases for any one cell to develop a, onogenic mutation. However, published literature reviews find no correlation between cancer incidence and body size.
This relationship should be easily seen given the tremendous size range of mammals from the bumblebee bat at mere 2g to a blue whale at 190,000 kg. For example, cancer among wild animals (<5%) is typically far below the percentage for humans (20-30%) irrespective of body size. Percentages in wild animals can approach 80% as in the Tasmanian devil or woodchucks but have very specific causes. In the later case of woodchucks, cancer is connected to a hepatitis virus. For cetaceans, and especially baleen whales, both large and long lived, we expect the incidence of cancer to be high. Cancer rates are high in belugas in the St. Lawrence estuary but related to agricultural and industrial pollution. However, belugas represent a rare case in cetaceans, with one study documenting only 33 cases before 2002. So what accounts for this paradox? One potential reason is that we have undersampled individuals with cancer. This is not likely if we assume that all mammalian cells, despite the organism, are likely to become cancerous. If we assume a reasonable 2% carcinogenic risk and just account for differences in size and not lifespan, then conservatively a whale has
chance of having a cancer free life. If poachers didn’t kill them first, 96% of elephants would also have cancer.
So what accounts for Peto’s paradox?
And no this doesn’t provide justification for you cramming your pie-hole with more…um…pie.
I would guess that mammalian organisms have some mechanism to prevent cancer, and the resources they devote to that mechanism are decided by a trade-off between the metabolic cost of cancer-prevention, and the incidence of cancer. If bigger organisms have a big problem with cancer, they devote more resources to the fight, until cancer is too rare to be worth it.
If my model is right, then the equilibrium incidence of cancer across organisms with varying body sizes should be observed to be almost flat. If it is so observed, that’s evidence that some cancer-avoidance technique is in operation. Further than that, I cannot say.
Do the authors assume in the paper that the chance of developing into a tumor is the same for all cells? It seems reasonabel to say that small tumors will kill a small animal, but it takes time for a tumor to grow big enough in a big animal to kill it, and without angiogenisis, lots of the tumors won’t make it. But that does’nt seem to answer the basic premise of the paradox. Are blue whales riddled with small benign tumors, and the scars of small tumors that couldn’t make the jump to viability?
Also, it’s thought that as the ability to recognize and kill cancerous tumors increases, the chance of autoimmunity also increases. The closer to “self” that the immune system is allowed to recognize as “not-self” means more very “self”-like tumors will be recognized, but there will be some immune reactions to actual “self” proteins as well. Does the literature on the Peto Paradox ever correlate autoimmunity rates in differently sized mammals?
Derek,
The question, in context of Peto’s paradox, is whether larger organisms disproportionally dedicate more energy toward ‘cancer-avoidance’ to balance out a potential for proportionally higher rates of cancer. Your idea might float but it seems that the pattern might not be flat but rather negative.
Rep, they assume that probability of developing a tumor is the same for all cells. But the model they use would need significant changes in probability to account for the observed differences. Are blue whales riddled with small benign tumors, and the scars of small tumors that couldn’t make the jump to viability? Great question and one that would provide some support of the hypothesis. I have not seen anything that relates autoimmunity to body size, but admittedly I am new to the lit.
I don’t know Peto’s paradox, but does it consider the universal scaling of metabolic rate with body size? Basically, the flame of life burns hotter in smaller animals, so wouldn’t that help large animals?
http://jeb.biologists.org/cgi/content/full/208/9/1573
Of course nearly all processes scale with body size, growth, respiration, lifespan, and a variety of other physiological and life history factors. So if cell growth/division occurs faster in smaller organisms does this increase their rate of cancer. However, this may be balanced out by their relatively short lifespans or even their potential to reach a hypertumor relatively quickly.
Ultimately, you all have posed really great questions of which I don’t have any definite answers. Keep them coming and continue to post ideas!
What about the cancer stem cell hypothesis? I believe this name has been given to a few different ideas, so to clarify I’m referring to the concept that the primary cause of tumors is a stem cell which becomes cancerous (as opposed to a mutated cell that becomes more stem-cell like as it becomes cancerous).
I bring this up because I recall a review stating that, for hematopoietic stem cells at least, there’s wasn’t a significant difference in the number of stem cells between a mouse and a larger mammal, such as a cat (I’ll try to find it again, might take a while). So, if all mammals have a similar number of stem cells, and most tumors originate from stem cells, all mammals should have a similar incidence of cancer.
Excluding environmental effects, of course!
I can honestly say that body size vs. cancer rate never crossed my mind before (I’m a bit ashamed of that, actually). At first glance, Peto’s paradox makes perfect sense. But then, if even a fraction of the hypotheses that made perfect sense turned out to be true, grad school would be a lot easier!
… sorta like how old age diseases (eg. Alzheimer’s) aren’t selected for or against because they effect people when they aren’t likely to effect reproductive success?
Recent work published by Moon, et al in the current issue of Cell brings to mind another possibility. The mechanism for creating different T and B cells in different organisms are roughly equivalent. Each different T or B cell is specific for a different molecule or peptide (called an epitope). Adaptive immunity happens when individual T and B cells recognize epitopes on the cancer (or whatever). The actual number of T and B cells (the two cell types responsible for adaptive immunity) is a proportion of the body mass. Therefore large animals have many more T and B cells. Do they have many more different T and B cells? Can they recognize many more epitopes?
It may be that large animals have more immunity to your average tumor than small animals do, just because they have more T and B cells.