Thursday, January 12, 2012

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!


Alessandro Giuliani said...

A single molecule is neither liquid nor solid (or gaseous), simply we have states of matter only when we have ensembles of many molecules, in which the nature and strength of intermolecular interactions determine the melting point of the substance. This means that the aggregation state is an 'emergent' property of large ensembles of molecules that, even if can be predicted and modeled by single molecule features (the electronic distribution, the molecular orbitals..)have a meaning (and a reality) only as an ensemble property. Similar reasons hold for other phenomena as tides (one water molecule tide ?) magnetism and so forth.
The same happens in biology: heart contraction implies the synchronization of many many cells as for correct beating, knowing the mechanism of beating of a single myocite is not sufficient to get an explanation of heart synchronic contraction..the same is true for any organ physiology. Trivial ! Yes trivial, I agree, but strangely enough the classical way of thinking any explanation in biology is sketching some arrows linking boxes INSIDE a single cell, popolation level explanation simply are missed as not important or mere consequences of what happens inside cells. Adopting the same attitude in physics, thermodynamics or statistical mechanics would never have been developed.
Notwithstanding clear evidences of population based regulation of gene expression (two samples of the same tissue have correlation coefficients computed along the entire genome expression near unity (think one moment of what does it mean having 30000 points (genes) correlation equal to 0.98) while a single cell has a nearly stochastic expression) and the simple consideration only around 200 tissues (and thus possible stable profiles) do exist out of the transfinite number of expression profiles coming from 30000 genes each varying around four order of magnitudes of expression nly a minority thinks a mesoscopic level of analysis is relevant.
We continue to think anything happens INSIDE each cell and the rest is pure averaging and summation..this is the point of TOFT, TOFT is a field theory, it is 'statistical mechanics', it takes into consideration the fact we are dealing with the coordinated behavior of millions of cells, so we must assume as the 'relevant layer for explanation' cell populations.
A big load of mutations can provoke cancer ? Surely yes (even if need more than one cell affected..) but this is not so relevant, the same can happen without any mutation (mutations come after for disregulation)a lot of nongenotoxic carcinogens are out there, the relevant point is that we must shift our attention to the question 'How a cell POPULATION changes its development trajectory going from one attractor to another (sub) attractor in the pahse space ?'
In this respect TOFT in my opinion is a necessary change of paradigm giving it allows to ask the right questions at the right scale.

Ken Weiss said...

I think nobody believes that a single gene causes cancer without some TOFT component. Cancer cells fail to respond properly to their internal or external environment. This then gets out of normal histological control. There are some clear examples of 'genetic' change (BRCA1 mutation, RB mutations, HPV viral insertions, etc.) that seem causal in this sense. Multiple other events may need to happen before there is a tumor.

In this sense, many different causes or, more likely, sets of causes, lead stem cells of various kinds--cells that are prepped to divide and differentiate into particular mature cell types for their tissue--to respond harmfully relative to the usual environmental information for their particular tissue.

Genetic mutations would be, and I think clearly are, the kinds of change that can lead to this.

So while one can argue about which theory, SMT or TOFT, is the right one, the more biologically likely answer is that cancer is a condition of cellular mis-response to context, and the age pattern suggests that multiple things must go wrong for cells to become clinically out of control.

Something like that, at any rate.

Alessandro Giuliani said...

In fact the point is that we are dramatically failing at both cure cancer and predicting carcinogenic potential by genotoxicity testing.
This implies we need another look at a different scale, even thermodynamics in principle could be derived by a Newtonian theory based on the encounters of different particles but this is not a productive way, much better to rely on ensemble emerging features like pressure, temperature and volume, don't you think so ?

Ken Weiss said...

I agree (though not an oncology specialist!). The idea of thermodynamic approaches, or statistical mechanics as another way to put it, is one we've recently written about (perhaps not in MT, but in the journal Genetics in 2011. If you write me I can send you a pdf, or you can get it).

I feel that aggregate analysis may be more likely to be useful to understanding the basic causal landscape and so on. But that doesn't make it very useful in individual prediction.

And there's another problem, I think. Unlike such principles as the Ideal Gas Law, which exemplifies statistical mechanics, the internal agitating components are not identical. Two canisters of argon may be similar in that all argon molecules are the same. But each person's genome is different. So we have an additional kind of heterogeneity problem.

But for many reasons that Anne and I have written about, an approach that uses concepts like aggregates (in Newton's honor, we suggested the term genomic 'flux'!) may be more useful than a genetic-enumeration approach.

Barry Barclay said...

I recently sent my paper on a novel mechanism for breast cancer to Dr Sonnenschein who suggested that I join this discussion. I'm afraid that I am one of those scientists that still believe in paradigm shift as the goal of one's life's work. Many cancer papers these days to me describe feats of great technical virtuosity but contribute only incrementally to understanding of the fundamental nature of the disease or its' etiology. In my view cancer could be considered an emerging pathogen and subject to the same driving forces in evolutionary biology as any other life form.
In the case of cancer the two important principles are the generation of genetic novelty by mutation (conversion of numerous proto-oncogenes to their oncogenic form) and the creation of new genomic linkage relationships by recombination Thus cancers are initiated by events which cause greatly increased rates of both mutation and recombination. In my model I suggest that this may come about by dysregulation of a molecular switch, the gene encoding thymidylate synthetase (TYMS). I would be happy to send a copy of the paper to anyone who is interested.

Ken Weiss said...

I'd like to see the paper. I think this is a terrific kind of discussion to have, so long as it stays exploratory rather than polemical or advocational!

If I understand your brief message, cancer is something somatic, then it's evolutionary and could have properties you describe, but that would be intra-individual rather than heritable. If it were a virus and got into the genome in the right (carcinogenic) place or something, it would have to make it into the germ line. There is more than a brief comment about what that would imply, relative to inter-generational evolution, but one could see ways it could happen, esp. if it could be transmissible in other than germline ways. However, it would be opposed by standard natural selection among individuals as much as favored by cellular selection within.

I think we know rather clearly that genetic changes, heritable and otherwise, do contribute to or even 'cause' cancer. There seem to be TOFT-like etiologies as well, of course depending on one's definition.

I believe that cancer's origins and life-history are somatically, as well as classicly evolutionary, the latter in the sense of transmission of contributing genes that can increase risk but only to an extent not purged by selection.

I think life is generally a spectrum of multiple causes with a distribution of frequencies--in a recent review (Genetics, 2011), Anne and I suggest the term genomic flux to give the kind of idea we're thinking about.

Let me add one other thing, too. I entirely agree with you about what most science is about. The pressures of careerism and the challenge to keep going and yet to make major findings lead to this.

I agree that at least basic science should be about understanding basic properties of nature. But I personally really resist the term 'paradigm shift' because it seems too often used and should be reserved for the real shifts such as due to Copernicus, Darwin, and the like.

Still, the idea that we already know what causes cancer and all we have to do is hammer out the details is another kind of over-done self-confidence. If peoples' lives depended on my work (e.g., if I were a clinician) I might be desperate enough for better treatment options that I'd say full speed ahead with GWAS or other similar incremental gains.

But I think we can see that they are limited and yet the pressures are to keep plowing the same field. So fresh looks are in order.

We hope MT can be a stimulus for that....however flawed our own personal ideas may be!

Alessandro Giuliani said...

Dear Ken,

I must admit I do not understand your argument when you say each person's genome is different, this is clearly true, but I was intending the dynamics of different cells INSIDE a given person. Even different cells are each other different but this case of stochasticity is exactly what must be approached by a collective analysis, the nature of different cells stochasticity in the arising of the collective organization we know since centuries and giving rise to organized and recognizable tissues is exactly what we need to investigate, in the following links I attach some works of mine dealing with this approach:

adopting techniques reminescent of renormalization groups typical of statistical mechanics. But you will find much more in looking at the works by Sui Huang group.
This is a paradigm shift in the sense the attention is diverted from INSIDE single cell to AMONG CELLS organization as the most relevant layer of explanation. This is in my opinion very natural giving tumor has to do with multicellularity.
I would be very happy to read your Genetics paper, so pls send me to my e-mail address you will find in the above papers.

Ken Weiss said...

Thanks. It is certainly about differences among cells within a person. I think that some of the known 'cancer' genes have to do with response to the cells' environments. BRCA1 is in a mutation-repair system, and the causal effect of mutations is that it allows mutations to accumulate in cell lineages, and those will presumably be related to the cells' response to environment. So I am not sure what the difference is.

Perhaps a major issue here, that might be semantic, is whether a cancer is a clone of cells, descended from a single aberrant cell, that may then entrain other genetically normally responding cells--to provide the tumor lineage with vessels, supporting tissue, and so on. And of course the tumor clonal lineage continues to accumulate new genetic change.

All of this is consistent with TOFT-like properties in that an ecology of 'abnormal' tissue evolves in the body--normal for itself, perhaps, but abnormal for the host.

How statistical mechanical-like concepts arise in your view isn't clear, but I will have to look at your papers.