Cancer Research

Is all cancer caused by red bone marrow?

This article offers a potential explanation for "Peto's Paradox", which poses the puzzle of the lack of correlation between cancer risk and animal body size. For example, assuming all proliferating cells have similar probabilities of mutation, whales with some 1000 times more cells than a human should all die of cancer (but they don't) and mice should almost never get cancer (especially given there's less time to develop cancer during their shorter lives, although this would be at least partly offset by their higher metabolic rate), yet 46% of wild mice die of cancer in protected laboratory conditions.

But the obvious resolution of this supposed paradox is that all cells are not equally likely to mutate into cancer, and those cells that are likely to do so don't scale linearly with body mass (i.e. with the total number of body cells). This indicates there may be certain parts of the body that initiate all cancers (even though they may then spread elsewhere), and given sharks - which have no bone marrow - very rarely get cancer, bone marrow seems like a potential culprit, especially since most red bone marrow is in flat bones, which scale with the square of body dimension rather than the cube as body mass does (which could explain why people who are taller, as distinct from heavier, have a greater risk of cancer). The lack of red bone marrow seems more likely to explain sharks' low rates of cancer than the active presence of cartilage, for which sharks have been killed in the mistaken belief that cartilage can be used as an anti-cancer treatment.

In the rare case of shark cancer shown here, you can see it seems to be coming out of its teeth & mouth, which I suspect indicates the cancer extends from its unique Leydig's organ, which is wrapped around its oesophagus (throat, but I doubt the researchers got a good look into its mouth to check this!), and like red bone marrow, produces red blood cells, as well as contributing to its immune system. Very little is known about exactly what the Leydig's organ does, but based on my very brief research, it seems that red bone marrow, and I assume also the Leydig's organ, are able to rapidly generate new blood vessels through cell division & replication ("angiogenesis"), as opposed to the initial "de novo synthesis" (through "vasculogenesis") of endothelial cells (lining the walls of blood vessels), which don't require pre-existing blood cells for division and are considered genetically more stable than cancer cells.

It makes sense that angiogenetic cell duplication would create a cancer risk ("tumor angiogenesis"), because when you photocopy a copy, and then copy that copy etc., eventually you lose some of the critical detail and have to go back to creating an original from its blueprint. So it stands to reason that repeatedly duplicating angiogenetic cells are more likely to develop mutations and start to replicate out of control (i.e. as cancer).

The main places where a shark's red blood cells are made are in the spleen and the kidneys, and I suspect that these produce them more slowly than the Leydig organ - perhaps through "vasculogenesis" - which is sufficient for it generally because sharks grow slowly compared to bony fish (& most mammals, I think), but a shark's need to constantly & very rapidly grow & replace its teeth (every 8 days, starting from local stem cells) may explain why it has the Leydig's organ near its mouth (& cancer at its teeth). I guess the Leydig organ may also enable sharks to rapidly produce red blood cells and hence maintain high hemoglobin content in their blood during exertion, and it would make sense to have that production near the gills (where this fresh blood can absorb oxygen), as it is.

To some extent, these ideas are already used in the treatment of certain "blood cancers", such as leukaemia, lymphoma and myeloma, when chemo or radiotherapy is used to kill cancerous blood cells and then these are replaced with fresh stem cells, which enable your marrow to create new healthy blood again (initially, I assume, from the "ideal" template through vasculogenesis). However, I am suggesting that all cancers ultimately come from angiogenetic blood vessel cells, which seem to grow from endothelial progenitor cells (EPCs) that are produced by bone marrow and then circulate around the body where they may develop into blood vessel cells through vasculogenesis or angiogenesis (with a risk of causing cancer in the latter case). By this theory, the longer that these angiogenetic cells reside in the body, the greater the risk of them duplicating until they mutate into cancer. As older people have less red marrow and more yellow marrow (presumably as they have little need to grow), their rate of refreshing these cells will be lower, and hence the risk of cancer rises (unless more white blood cells to fight this are produced from yellow marrow that develops as immunity increases with age - noting that cancers such as leukemia & lymphoma are associated with abnormally high levels of white blood cells, so leukemia may be more common in children as they haven't developed enough yellow marrow to generate sufficient white blood cells to stop the cancer growing). Notably, both tumour cells and red blood cells have the same signalling molecule "CD47" on their surface, which protects them from being attacked by the immune system. A link between bone marrow & cancer is also consistent with the fact that breast & prostate cancers often spread to bone marrow and bone-marrow fat cells seem to help tumours grow.

Further, I suggest that a key cause of cancer anywhere in the body could be the blockage of capillaries - e.g. by fat or smoke particles (or dehydration from excessive salt consumption) - which could also inhibit the renewal of angiogenetic blood vessel cells and result in them staying in the body long enough to mutate into cancer. Blockage may also be more likely in the extremities of the blood network in the skin's dermis layer, especially if the skin is dried & damaged by sun exposure or other environmental factors (which a shark is well protected from with its tough bony skin). There is also some similarity between this concept and the blockages that are involved in mastitis, which has symptoms much like inflammatory breast cancer. Not surprisingly, recent research finds keto diets - which reduce body fat and glucose levels - can restrict the growth of certain types of cancer, which I guess may be partly a direct result of fat reduction as well as inhibiting tumour blood-supply (through "anti-angiogenesis").

In general, larger animals usually have a lower metabolism, with bigger and slower-dividing cells, which may suggest they produce less angiogenetic red blood cells, thus having a lower risk of cancer than their body size (and total number of cells) might suggest (e.g. only about 5% of elephants die from cancer, vs 20% of humans, despite elephants having 100 times as many cells). However, the mole rat is another animal that rarely, if ever gets cancer, and its features seem consistent with my hypothesis. Unusually for its small size, this rather ugly creature has:

Some research suggests that animals with surprisingly low cancer rates have developed superior cancer-fighting genes, so why haven't we? Well actually we have to some extent, because there are examples of patients who after being treated locally for cancer in the femur (which has bone marrow), the immune system was able to kill off the further cancer throughout the rest of the body (a rare phenomenon called the "abscopal effect"). This indicates that the development of cancer is actually a battle between its rate of growth and the rate at which the body can attack and reduce it. The relationship between metabolism and cancer growth rates is also indicated by research on diets, and cannabis use (which increases metabolism, possibly increasing the rate at which cancer-prone red blood cells get refreshed before they can mutate). A tumour smaller than a metal ball at the end of a ball-point pen is generally considered harmless, but larger tumours, like any organism, need new blood to grow (see also here), and past research has suggested that tumor growth is angiogenesis-dependent (prompting studies of cartilage as a potential source of angiogenesis inhibitor drugs). It may be, however, that new blood flowing through new blood vessels is not just a food source for tumours, but also a supply of further mutated, cancer-prone angiogenetic cells.

Ultimately however, the reason humans struggle to fight against larger tumours is because we don't need to; in fact on the contrary, it would be an evolutionary disadvantage. Humans are designed to grow and reproduce reasonably quickly, and once children can survive on their own, the continued life of their parents is - from evolution's perspective - simply a waste of precious natural resources (like food) that would be better allocated to younger people. For us to survive and evolve as a species, we must, individually, die - preferably as soon as we are no longer useful to the species. Animals with slower metabolic rates both can and need to survive longer in order to reproduce and sustain their species, so they are less susceptible to cancer. For example, the Greenland shark grows only 7.5 mm per year and can live for 500 years, but the female doesn't reach sexual maturity until she's 150! Dogs on the other hand, with a much shorter life-cycle than humans, are highly prone to cancer. The advantage of faster generational turnover in humans (who have a natural lifespan of only 38 years and commonly less historically) is that we can/could evolve faster and thus better survive a changing environment. Obviously now we'd like to challenge nature's rapid life-cycle, but should we? It might make sense if we had reached a level of evolutionary perfection and had a stable balance between population levels and the environment, but I see little evidence of that yet (especially with regards to our psychological/emotional development).

Nevertheless, if my hypothesis on the cause of cancer is correct, then one potential cure could be to not focus on trying to attack cancer cells, but rather to somehow promote the generation of "de novo" blood vessel cells (through "neovascularization") and then rely on the body to automatically reduce the replication of higher-risk angiogenetic cells, because they are no longer required (since normal cell supply is usually regulated as needed). This could reduce the supply of cancer-prone blood cells and give the immune system greater opportunity to attack and reduce existing tumours. This is a subtle variation on the approach described here, which says, "Cancerous tumors also grow new capillary networks. One approach to fight cancer is to starve it with drugs that block angiogenesis". However, the effectiveness of antiangiogenic therapy is "rather modest". Presumably one disadvantage of antiangiogenic therapy is that it inhibits the renewal of blood vessels throughout the body, not just within tumours (& hence is likely to produce side effects such as impaired wound healing), thus limiting how intensive the treatment can be. Perhaps the approach I propose could sidestep this problem, possibly in tandem with recently developed immunotherapies. It at least seems an area worthy of research.