Further notes about the morphostasis concept – split files

(43) Most cancers are just 'bad luck'

There is currently (new year 2015) a great deal of discussion around a study published in Science that is titled "Variation in cancer risk among tissues can be explained by the number of stem cell divisions." The authors reach the following conclusion, "These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to 'bad luck', that is, random mutations arising during DNA replication in normal, non–cancerous stem cells." This was in the editor's summary, "Remarkably, this 'bad luck' component explains a far greater number of cancers than do hereditary and environmental factors."

This has led to a welter of comments including:

[BBC] "Most types of cancer can be put down to bad luck rather than risk factors such as smoking, a study has suggested. ..//..The results, in the journal Science, showed two thirds of the cancer types analysed were caused just by chance mutations rather than lifestyle. ..//. . The study shows that two thirds of cancer types are simply chance. But the remaining third are still heavily influenced by the choices we make."

The science reporter goes on, " .. old tired cells in the body are constantly being replaced with new ones made by dividing stem cells. But with each division comes the risk of a dangerous mutation that moves the stem cell one step closer to being cancerous."

Now, this is all very strange and there is (in my opinion) something wrong with the interpretation. Let me quote two passages from my unpublished papers.

From Morphostasis and immunity 1984: "Cancer is characterised by disturbed growth control and a reversion to an embryonic cell behaviour (retrodifferentiation). These conditions seem most likely to occur when regeneration and/or proliferation (eg, T–cells in 1ymphomas) are exuberant. There is an inverse relationship between, regenerative capacity and cancer in the animal kingdom and it is worth noting that carcinogens may induce supernumerary structures (eg, limbs) in lower phylae. Note that lymphomas will be relatively common in the years in which auto–rejection can become intense (16–45yrs) and also note that lymphomas will predominate over other cancers in granulomatous disorders because local regeneration is impaired."

From Clinical Morphostasis: "In mammals, this impairment of surveillance should occur either at the extremes of life or following prolonged focal auto–rejection and its consequent anergy. In the elderly, the increasing impairment of immunity coupled with the heightened susceptibility of epithelium to various noxiae (and thus auto–rejection) may predispose to a high incidence of carcinomas. Focal anergy on its own (consequent upon intense auto–rejection) may be a major cause of the predilection that certain cancers have to strike young adult to middle aged patients (eg, lymphomas, focal cancers like colonic cancer in ulcerative colitis and testicular tumours following mumps). In the very young there is a relative incapacity to reject tissue. It is worth noting, then, that the predisposition for epithelial cancers found in the elderly is not mirrored in the young. Cancers are relatively common in the very young and there is evidence to suggest that many regress before they reach clinical significance. Note that carcinoma–in–situ occurs more often than overt cancer, the abnormal cells tend either to be kept in check or are eliminated by lympho–monocytic cells."

This predominance of cancer in the tissues most exposed to high regeneration never tempted me into the same conclusions aired above (that the majority cause of cancer is just 'bad luck'). And this despite the prediction that highly regenerating tissue would be more susceptible. So why? It has taken me a while to escape my perceptions of the process in order to appreciate why the authors stated, "These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions." I think we need to take a step back and examine the paradigm that governs the interpretation of these observations. The traditional view of cancer is that it is a genetic disease caused by mutations. Traditionally, the acid test for carcinogenicity has been whether an environmental agent can cause genetic mutations in exposed cells (bacteria are usually used). There is no place in this paradigm for non–genetic causes. Every time a suitable set of cancer favouring mutations arise, they go on to produce a full blown clinical cancer. End of story.

This study appears to support the notion that particular tissues within the body are increasingly susceptible to the emergence of cancer as the level of regenerative activity increases ("appears" because I can't read the full original without buying it at a silly price). In dismissing environmental "triggers" as the dominant cause of cancers and substituting the frequency of stem cell divisions it conveniently ignores the point that such enhanced stem cell activity has either immediate (noxious) triggers or is an evolved adaptive and pre–emptive response to this noxious threat (shedding epithelium rapidly will enhance the clearance of noxiae). The underlying result is an enhanced auto–rejection and then replacement of damaged cells. This exposes the system to a heeightened prevalence of mutations.

The authors talk freely about "tissue homeostasis". Now, I think it is around this that the conclusions that many folk are reaching have been blown out of proportion. The majority of the stem cells that develop a mutation, that could lead on to cancer, are dealt with by a sophisticated tissue homeostatic process with its intrinsic surveillance for miscreant cells. Only a tiny fraction of these miscreant cells go on to turn into full blown cancers and the circumstances under which this happens is heavily influenced by age, inherited predispositions, concomitant disease, environmental factors and epigenetic factors. The original mutation, though generally necessary, is not sufficient to lead on to a clinical cancer. The failure of tissue homeostasis is the final arbiter on the emergence of clinical cancer. (Note how the individual cells from some teratomas can be cloned to produce normal embryos – hence I have qualified the statement by "generally" necessary). This paper from Rozhok and DeGregori is highly relevant to this point.

The short section on cancer and stem cells ""The danger theory: 21 years later" (unpublished section) makes all this a little clearer I think.

The BBC World Service have a nice little audio snippet about this. And, interestingly, this has just turned up in Cancer Research . Also, Researchgate currently (Jan–15) has a discussion on this Science paper to which I have also contributed . You may find more insights there.