Do we still not know what causes cancer? Part III

This series of posts is about cancer but also about the nature of life itself.

Do we still not know what causes cancer?  We've discussed the origin of the current theory of cancer, the SMT or somatic mutation theory.  As we outlined in Part I, this 50 year old view, that cancer is a disease of diseased cells that have been screwed up by genetic mutation, has focused almost all cancer research in one way or another.  It is relevant as well to a proper understanding of life itself, as we suggested in Part II.  Is the lack of progress in cause-directed (that is, gene-based) therapy, a result of a badly misdirected effort, rather than just the heavy challenge of targeting genetically altered cells?

The competing 'tissue organization field theory' (TOFT) is that cancer is a tissue rather than cellular disease, and goes roughly like this, as outlined by Soto and Sonnenschein (hereafter, SS)  in the May 2011 BioEssays point-counterpoint that triggered this series of posts:

SS point to several aspects of cancer that do not reflect simple genetic causation, or simple one-cell-gone-bad-on-its-own  model of causation; the latter is what they, very inaptly in our view, imply is the heart of the SMT model.  Experiments show that a single transplanted cell cannot generate the multiple cell type architecture of the organ from which it was taken.  Sometimes cancers regress, or a transplanted cancer cell can integrate into a normal tissue architecture in the recipient organ without proliferating as a cancer.  That means that the cell is not, in these experiments, inherently abnormal as might be expected on a genetic model, assuming no experimental artifact.  Some tumors regress upon  hormone treatment, again showing that their abnormal behavior may be a matter of signaling and that it can be reversed or slowed by changing the signaling environment: the cell is not inherently mischievous.  Some normal cells can become cancerous if transplanted to some other tissue context, showing that mutations are not needed.  Environment may not be everything, but it's not nothing, either.

Further, SS point out that interactions among the different types of cell in a tissue cannot be reduced to individual cellular events.  That seems wholly correct, and shows the clearly relevant 3-dimensional architecture of tissues.  Most cancers arise in tissues that include both supportive (stromal) cells and actively dividing organ-specific functional (parenchymal, often epithelial) cells, and that these must interact in normal as well as abnormal tissues.

The figure is from the SS paper showing their idea of how context affects tumorigenesis.  Of course, they want this to be a tissue-architecture phenomenon in which the 'carcinogenic event' is not a genetic mutation.  They may well be right that many triggering events are not themselves mutations (but the SMT asserts that induced by the event to proliferate, the cells become vulnerable to mutation).  In any case, one could offer the same figure for events that are mutational, because of course once a cell does not respond to its environment properly it could be induced to grow in undisciplined ways for that tissue, as cancer cells do.

SS seem to criticize the genetic theory of cancer because tumors of the same organ from different patients seem to involve different sets of mutations, as if variation among cases (and imperfection of mutation detection methods) means that the SMT is an erroneous view.  Of course there are limits to what kinds of mutations can be detected in complex cancerous tissue (that also contains normal vessels, nerves, and so on), but in a polygenic view of cancer, as a complex trait involving many genes and signaling pathways, like other complex traits,  this variation and multiple gene involvement is not a reflection of a wiggling, erroneous theory, but is just what one would expect.  No geneticist we know thinks otherwise, even if they may want simpler answers (as many GWASers do).

SS focus their discussion only on 'sporadic' cancers, that is, ones without a family history of the same tumor type.  That is a completely false, indeed naive, dichotomy.  Most if not every cancer, being a polygenic trait, will involve some inherited risk components, even if GWAS or whole genome sequencing of tumor vs host-normal tissue can't detect weak effects.  SS are quite wrong that most 'inherited' cancers are early onset or pediatric--they are not including the multigenic effects, so theirs is a quite restricted view.

According to SMT, cancer is a disease of sick cells in a normal environment.  But in TOFT, it is a disease of normal cells in a sick environment.  The SMT is a special case of genetic evolution because modified genomes can be inherited but, since cancer is a disorder of tissue architecture, abnormal tissue architecture cannot--a fertilized egg has no tissue!

A recent and very informative installment of our favorite BBC Radio4 program In Our Time discusses macromolecules, and we posted on that separately, starting here.  But this installment just casually drops an observation about biomedical applications of macromolecules that is relevant here.  Webs of supporting tissue can now be constructed of synthetic macromolecules, and embedded with stem cells, then placed in context to repair skin, trachea (windpipe) or other types of tissue, where the cells flesh out the matrix which develops into normal tissue.  The casual comment is that each application requires a different artificial matrix, because stem cells respond differently to different substrates.  Clearly context matters!

We scientists are vain and we all want to be part of a major 'paradigm shift' in our respective fields--we want to be important, to live in important times, and to be the architect of a grand transformative event.  So it is common that we want to suggest (and, of course, name) new sweeping theories.  That may sometimes be correct, as it was for Newton, Darwin, Einstein and others of their fortunate and insightful ilk, but that's very rare, and it is usually uncalled for.  TOFT vs SMT oversimplifies what seem to be overlapping phenomena related to cancer--and, indeed life and its evolution itself.  But there is no conceptual revolution involved.  Cells induced by whatever means to misperceive or or respond wrongly to their signaling environmental context can go off on their own, until correct in some way, or in some instances can get out of any such control.  There's no reason to be surprised at that.

SS, hinting perhaps that they are paradigm-shifters themselves, conclude by citing some philosophers of science and using that to criticize the revisions that SMT advocates regularly make in their theory as the result of experiments that, SS argue, support TOFT instead.  There is an exchange of barbs in the September issue of BioEssays, but it adds nothing of substance to the discussion; there, SS again sneer at changes in the SMT theory as 'changing the goal posts', but indeed that is exactly what any valid theory of life (or any area of science) must do as more is learned.  It is only a valid criticism if the fundamental aspects of the theory are abandoned, but this is not at all the case.  Indeed, as the exchanges show, the SMT is only strengthened--especially if one takes context into account, as it must.

In our view, nobody can deny the importance of context or even that cells that are mis-informed about or that mis-interpret their environment can launch out-of-control growth.  But SS seem again to suggest that geneticists are holding essentially to single-gene concepts of causation, which as we noted above we think no sane geneticist does--even if some mutations may make individually strong contributions to risk. After all, BRCA mutations do that, yet nobody thinks the tumor waits 40 or more years to show up except because other events must also occur (indeed, BRCA genes are involved in mutation repair!).

But such philosophizing is irrelevant if not self-serving baloney!  Every science is always imperfect, and always under revision as new facts become known.  Whether the revisions in SMT are cogent is a separate question, but revision itself is not a fault.  Likewise, SS basically ignore the huge wealth of evidence of clonality and the many clearly known mutations relevant to cancers (in a sense, they don't even try to revise the TOFT).  None of this means we have 'the' answer, because there may be no single answer.  These are not dichotomous, incompatible views of abnormal cell behavior. 

In the end the SMT theory, that cancer can and usually does involve genomic mutations, is completely defensible, as Vaux very powerfully shows in his part of the BioEssays exchange.  This doesn't mean cancer is just a disorder of isolated cells!  Naturally, context must matter.  And, instances of cancer cells becoming normal, or not leading to cancer when transplanted into a normal context, shows that SMT can be oversimplistic.  But a polygenic view of cancer at the cell level is totally consistent with both.  Mutations are involved, but cancer is a disease, at least in part, of mis-cooperation--aberrant signaling or response to context.

We can't resist our own vanity in pointing out that in and around 1990, I had suggested in several papers and a book a somatic-polygenic etiology for cancer, in terms that for the specifics known in its time were essentially modern conceptually, and that were consistent with a contextual yet genetic idea of the nature of cancer.  The idea was compatible with what we know (and knew) of epidemiology,  genomic evolution and causation, and that cancer is a disorder of misbehaving cells, involving gene networks.  A similar view is the bottom line message of MT, the book.  A  mix of somatic and inherited genomic architecture involving multiple contributing genes, in a tissue context stimulated by non-genetic environmental factors such as mutagens and stimulants of cell division, provides a consistent if not simplistic view of cancer, because it puts cancer into the context of normal biology and its geological as well as somatic evolution. 

False dichotomies here, as so often, reflect yearning for simple explanations for complex phenomena.  In fact, what we clearly know about the nature of genomic action, and the essential role of cooperation in the making and maintenance of multicellular organisms, shows that we need no all-or-none 'theories'.  We just need to view cancer as a phenomenon in the kind of biology we already know very well.  That there will be variation in the trait and its cause is exactly what we expect.  So is the fact that causation can be difficult to attribute to individual factors.  That we cannot simplify polygenic phenomena is an apparent reality.  It's not a matter of one wrong or right theory.  It's a reflection of how life works!