New findings in cancer research: Something old and something new

A story in the NY Times, a report from the annual meeting of the American Association for Cancer Research, suggests that cancer may be a different sort of disease than has been assumed.  It has been thought for several decades that cancer is a genetic disease, due to mutations that lead malfunctioning genes to cause a single cell to divide uncontrollably. The mutations cause the cell to divide rapidly, and at the same time, override the normal mechanisms that limit cell division.  One of the signature discoveries of the 1970s was that tumors in a person are usually clonal: they derive from a single 'transformed' cell.  That made cancer a 'genetic' disease at the cell level. 

Melanoma cells invading the brain

However, the story points out that recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be "even more willful and calculating than previously imagined", if you want to accept the usual hyperbole and anthropomorphizing. This story raises the possibility that there are additional mechanisms, including many kinds of RNA that are not the classical protein-coding parts of genes that textbooks (at least, out-of-date textbooks) describe as how the genome works (that is, not just due to misbehaving messenger RNA), as well as signals from the microbes that colonize our bodies.

Microbes comprise maybe 90% of the cells in our bodies, being integral to digestion, and other functions.  They need us and we need them, and this co-existence is maintained by communication between our cells and our resident microbes.  When this goes awry, our cells may be signaled to begin to divide; this aberrant signaling may be responsible for cancers of the digestive system -- the colon, stomach, and esophagus -- and perhaps other organs.

Another possibility is that segments of the non-coding DNA that makes up maybe 98% of our DNA may send aberrant signals that lead to uncontrollable cell division.  Pseudogenes, or remnants of gene duplication events long ago that on their own now have no function, or garbled function, may be one of the elements in non-coding DNA that incite uncontrollable cell division.

And finally, micro RNA may inhibit or alter the normal working of messenger RNA, disrupting normal cell signaling.  It has become apparent in recent years that micro RNA has a function in the regulation of much normal gene expression, but it seems that it could also be involved in the kinds of abnormal cellular functions that lead to cancer.  It's possible that pseudogenes interact with microRNAs to do this.

Well, these alternatives are clearly all possible, but unfortunately the story is the usual type of overkill and melodrama that we see every day in the media. Investigators making exaggerated claims of new discoveries, rather than simply reporting additional facts and mechanisms that are being found.  Contrary to the sense of the story, nothing in these new findings challenges the basic current idea about cancer, even as they make it clear that the usual approaches for finding genes 'for' cancer, such as genomewide association studies (GWAS), are generally not going to work. 

And indeed, there may be some mechanisms that cause cancer but do not alter DNA or create abnormal cells.  Instead, such mechanisms may simply induce genetically normal cells to respond to their environment in ways that are mistaken (relative to the survival of the organism).  These included some apparent context responses that should lead as a rule to many cells misbehaving in the same way -- polyclonal tumors, in which not all cells are derived from the same single misbehaving ancestral cell.  That was an older idea about cancer that hasn't had much credence for several decades.

Cancer is clearly a nasty problem for an organism, and one that involves evolution on the scale of one's individual lifetime, with some similarity to long-term evolution of species.  If cancer were to turn out to be polyclonal, it would make it more like infection, in which the body is occupied by descendants of many different infecting bacterial cells or viral particles.  Since the descendant cells of each founding cell will then undergo their own evolutionary history, attacking the tumor would become more difficult -- the tumor cells wouldn't share the same characteristics to the extent that a single clone of cells do.  The evolution will not be of a single tree of descent.

Viral cancers can be polyclonal if the virus independently transforms different cells in the individual, but this seems unusual.  Also, if only a small number of changes are required, and the person inherits one or more of them, and has many cells at risk of somatic mutations to generate the rest, there may be several independent tumors in the same person.  There are some examples of this.

But generally, the standard model of a mix of inherited variation that makes a cell less likely to respond normally, complemented by somatic mutations that finish the job of producing a single, badly programmed progenitor cell, seems basically safe.  Even if, as seems to be the case, we're finding new aspects of the genome and its behavior that are involved in the production of such a cell.