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!

Do we still not know what causes cancer? Part II

Part I in this series described the SMT, or somatic mutation theory of cancer.  The original theory was developed from some data on both the epidemiology and the known cases of inheritance of cancer susceptibility.  It lead to a focus on the idea that, at the cell level, cancer was a misbehavior disorder due to mutations--changes in DNA--in genes whose normal function was critical for the cell type in question--be it lung cells, intestinal cells, or other tissues.  The cell can't behave properly if its relevant genes have been changed.  The idea is then that a given case of cancer is due to the spread of a clone of cells, descended in the person's body from a single initial 'transformed'--misbehaving--cell, and cells in that clone then accumulate a diversity of subsequent mutations.

Tests of clonality and searches for mutations have been done, and these have been successful.  Similarly, genomewide tests have shown that cancer cells, relative to host normal cells, do reflect many mutational differences.  At least some of these are repeatedly found, and are in genes related to cell division and other relevant aspects of behavior.  Some of these changes can be inherited, leading to elevated risk, as we described briefly in Part I.  The picture was complex--essentially, polygenic, with different tumors manifesting different mutations.  Still, patterns of mutational change have been shown to be relevant to response to therapy and prognosis.  It all seemed consistent with the SMT.

However, there were some weak points in the data.  Normal cells also show mutations, and cataloging the differences from tumor cells is difficult.  After all, even under the SMT, normal cells would be expected to show mutations in the same genes found changed in tumors, because that's how the combinations of 'bad' changes accumulate.

Further, a 'theory' of the essential qualities of life, that goes beyond our contemporary obsession with Darwinian selection and genetic determinism based on competition, such as we try to discuss in MT (here, and in our book of the same name), stresses the role of complex multi-component cooperation in the nature of life among organisms, species, and cells.  Signaling interactions are a fundamental property of that cooperative aspect of life.  A cell's behavior is instructed by its current constituents (including the genes it's using at the time) and the conditions it detects in its environment.  What it detects alters the genes it will express or repress.  A stomach cell expresses appropriate genes for stomach-related behavior, but not genes involved in, say, liver, brain, or blood.  When the environment changes, the cell changes its gene expression and its behavior (thus, when a stomach stem cell detects the absence of adjacent differentiated stomach cells, it divides to replace the lost cells.

What we know about such complex phenomena is that they typically are polygenic, that is, are affected by many genes, and their variation can be due to many different combinations of variation in those genes.  This is what we write a lot about, for example, in the context of GWAS findings.  In our view, to this extent, cancer like other complex traits, is a polygenic phenotype involving cell-to-cell signaling as a determinant of the complex structure of organs like lungs, skin, brains, and ovaries.

Thus, a key feature of life is properly timed preparation, detection, and responsiveness of cells.  Once it becomes committed to the environment it has been prepared to detect, or to whose changes it detects, it is channeled in particular directions....and its set of expressed response detectors (signal receptors, for example) limit what it can do in the future.  In a polygenic view of tissue behavior, there would be many different ways to go awry.

Viruses and other cellular components, normal and from the outside, can also enter the genome or pop  copies of themselves elsewhere in the genome.  This can lead to abnormal effects on the regular genes in the vicinity of the genome where such a copy has, by chance, landed.  For example, a gene may be induced to be expressed abnormally as the result of such events.  This is not a mutation in the expressed gene itself, but in its anomalous usage.  But once the transposed bit of DNA is there, the cell and its descendants are doomed to obey its effects!  It is, in a sense, a kind of somatic mutation, but would never be detected in sequencing the affected gene itself.

The May 2011 BioEssays point-counterpoint includes one part, by Vaux, defending the SMT, but opposed by Soto and Sonnenschein who argue for a tissue organization field theory (TOFT).  One need not accept all-or-nothing combative 'theories' to ask whether we have somehow misinterpreted the SMT, leading to a research focus that will have only limited success, if based on the expectation of mutant genes as the cause of cancer.  That can be important, of course, in the research approach to effective therapies. But it could also be important in what we understand about genetics....and even about evolution and life itself.  That's because we might have been too deterministic in assuming genomes to be self-contained 'programs for life'.

This can be of fundamental importance for understanding life, far beyond its relevance to cancer.  That's because cooperation among genes and other cellular components, rather than gene structure itself, may provide the critical explanation of cellular behavior--even if genetic variation indubitably would be one way to affect that cooperation.  In part III of this series, we'll discuss the basic ideas underlying TOFT.

Do we still not know what causes cancer? Part I

Many theories have been proposed for the causes of cancer.  We were involved in some of this work, long ago, before molecular approaches were possible.  We were present when various immunological and other theories were being displaced by a genetic theory, and that theory has been developed over the years.  Cancer is an evolutionary as well as genetic phenomenon, but it's the evolution of genetic variation among cells within the body.

A few observations, too much to go into here but involving a fairly rare childhood eye cancer called retinoblastoma, led to the idea that one could inherit susceptibility mutations (variation in particular genes), but that that required waiting for other mutations to occur somatically, that is, in body cells as they divide throughout life.  Three of the key bits of evidence were, first, that frankly inherited susceptibility seemed rather rare (and it still does, for most types of cancer), even if inherited variation contributes to risk.  Second, it was shown by some clever early experiments that cancers are clones of cells within the affected person's body: the tumor began as a single 'transformed' cell.  Third, the risk of cancer rises with age in a way that seemed consistent with waiting time distributions; that is, a person had to 'wait' until some single cell was transformed, to become the progenitor of the tumor as it grew and sometimes spread around the body (metastasized).

Together, these facts suggested that cancer was a multihit, mutational disease.  It was a genetic disease because the progenitor cell was transformed by mutations.  It was clonal in that this single cell led to the entire descendant set of cells that comprised the tumor.  And it was multihit in the sense that many different mutations were required to transform a cell.  This was the somatic mutation theory (SMT) of cancer, which is what we ourselves worked on when we were in Texas long ago.  The idea is that cancer is a disorder of the cell itself, a damaged cell that did not behave properly in its context.

The age pattern of cancer--how fast risk increased with age--could be associated with the type of tissue.  Carcinomas grow in dividing tissue.  In most organs, partly differentiated stem cells divide and become terminally differentiated for their type of tissue (stomach, intestine, etc.).  When the differentiated cells died or were sloughed of, the stem cell would divide and produce more terminally differentiated cells.  The tissue maintained its integrity because the cells had the right genes expressed, receptors on their surface, and so on, to behave properly for their type of tissue.  Stem cells were normally quiescent until stimulated to divide.  Somatic mutation released that inhibition and disrupted the orderly responsiveness, leading to the relatively undisciplined proliferation that is cancer.

The more stem cells at risk in a given tissue type, and the more their natural pattern involved dividing and differentiating, the faster risk would accumulate.  If cells stopped dividing in a person's natural life-history, tumors became rarer and rarer as the person got older.  The pattern was consistent, and the age-pattern of onset suggested that many mutational 'hits'  were involved.

Work using techniques that became available mainly in the 1980s was consistent.  Evidence of mutation in cancer cells compared to normal cells from the same individual implicated multiple different genes with (as in other complex traits), different sets of mutations in different tumors of the same type (lung, intestinal, etc.).  At the same time, some of these mutations could be inherited, if the person had inherited a good copy of the gene along with a defective one.  Then, one might have to wait for the bad-luck mutation of the other copy of that gene, along with some other genes.  That's why even strong risk-affecting mutations don't cause cancer right away; instead, you have to wait less time for some other complement of mutations to arise.

It was clear that tumors were clones by and large, but as they grew and spread, new mutations, often involving unstable, multiple chromosomal changes, would arise so that the tumor itself then was comprised of a tree of varying descendant cells.  When the right (for the cell, though for the victim, the wrong) set of mutations arose, some cells gained the ability to spread more rapidly, to invade other types of tissue, and so on.  The more potent cells could out-compete the more sluggish ones, in a kind of selection.  This became a kind of natural selection when drug therapy is applied, as some cells could survive the drug, leading to resistant tumors.  The population of tumor cells were mutant but they were still the host's own cells, which explained why the immune system, structured to detect invading foreign cells, was not good at finding and removing them.  Modern genetic analysis of tumor cells and normal cells has generally found evidence consistent with these ideas.

In this view, cancer is always a genetic disease and perhaps thus always amenable (in principle) to a genetic therapeutic approach:  find the mutant gene and target cells expressing it in ways that are specific, so as to leave the same person's normal cells unaffected.

This was, then, an evolutionary theory of cancer involving genetic changes in somatic cells, complemented perhaps with some inherited mutations.  It had most of the elements of Darwinian organismal evolution, including its basis in genes.  It fit the epidemiology, including the role of environmental factors--largely being those that induced mutations or stimulated cell division.    It is a theory we worked on, wrote about, and believed seemed consistent with the evidence (including, yes, GWAS studies of cancer, and various cancer genome projects!).  We even suggested somatic polygenic models of evolution among body cells as consistent with the age-onset patterns.

But this theory has been questioned on a number of grounds, and there are, as usual, alternative explanations.  These have been aired in a recent point-counterpoint in the May 2011 BioEssays in which the protagonists discuss serious questions about the somatic mutation theory of cancer.  The facts discussed above may apply, but they may not account for all cases of cancer....or perhaps the data have been interpreted in the context of an assumed theory and hence seemed to be consistent with that theory.....a bias we often write about here on MT.  Perhaps there are other kinds of causation.

We'll discuss those, as raised in the article, in our next post in this short series.