Thursday, December 31, 2009

Cancer as an 'environmental' disease -- a revolution?

Cancer and the environment
There is a very good story in the New York Times by Gina Kolata, one of their long-standing best science writers, about the nature of cancer as an 'environmental' disease. She lauds a paper by a Dr Mina Bissell some 20 years ago that, she writes, has proved prophetic.

Prophetic, but one might say that cancer has always been viewed as environmental in that it can be thought of as a set of diseases that arise because of exposure to mutagens, like cigarettes smoke, dangerous chemicals, radiation, and so on--as well, of course, as our old nemesis, chance (because mutations can always arise by chance).

The usual idea is that carcinogens cause mutations that lead cells to go out of control, locally forming a primary tumor, then sloughing off into the circulation to spread elsewhere in the body (that's a process called metastsis). These somatic, or body-cell, mutations are not inherited because they're not in the germ line (sperm or egg cells), but they are inherited by descendants of the mutant cell in the body. In this sense, at the level of a cell, cancer is a disorder of mutant cells going off on their own, an invasion of genetic aliens. The cell does this because its genes have been modified to make it not respond as a normal part of you as it should, but as a kind of genetic alien.

The cellular environment
But this story seems to be different. It's about the cellular environment. Kolata lauds work of several decades' standing that shows that cancer is about cells whose behavior is abnormal relative to the context of their local tissue environment. That is, the cells are not just bad actors per se, but bad in that they don't listen to instructions from their neighbors about how and when to divide.

This is just the kind of thing that our book The Mermaid's Tale is about--the way life works at the cell level, in which genetic messages regulate interactions and their dynamics in time and space. Cancer is a good illustration of these principles, of partially sequestered units whose actions depend on their sensing of their immediate environment. Cancer cells resemble the 'cytospecies' we discuss, referring to separately differentiated cells that, despite the same genome, behave differently to form our various tissues. That's how development works, and how it can go awry even in adults ('awry' for normal cells, but of course the mutant cells are having a proliferative blast at your expense!).

However, Ms Kolata refers to cancers that arise apparently as the result of other causes, such as injuries, in which cells become confused and misbehave not just because of mutation but because the event leads them to misperceive their cellular context. She quotes the much-overused phrase 'paradigm shift' in the lauding of Dr Bissell's ideas by an award committee. By itself, that's a mistake. There is nothing conceptually new or unusual about viewing cancer as a disease of context-misbehavior of cells. That is the prevailing view of cancer.

Dizzied into incoherence
Now, if anything is novel here, it would be that after injury the misbehaving cells are not mutant, but are just part of the person's genetically normal cells that, dizzied by injury into incoherence, start to express aberrant receptors or respond to signals from nearby cells in a way that is erroneous for that particular tissue type. But once confused in this way, the cell doesn't come to its senses and regain its bearings.

If that is the case, then cancer would be a disease of aberrant signaling not necessarily due to bad genes (mutated by environmental agents, chance, or inheritance), but to bad genetic behavior whatever the cause. If cellular life is complex, you can get screwed up in lots of ways, some by permanent genetic change, others by misunderstanding. Either way then, of course, you're screwed.

Some evidence that could be interpreted this way has to do with regressed tumors that never become lethal (we've referred to such evidence in commenting about the risks of over-treatment due to excessive 'diagnosis' by over-screening such as by mammography). Of course, there are other ways tumors, even caused by somatic mutation, could eventually be detected by surveillance mechanisms of various kinds. So, regressed tumors don't really give unqualified support to Bissell's ideas.

Another possibility is that the injury-induced tumors did, in fact, result because of mutant cells that by chance hadn't yet produced a tumor. It has long been the standard theory that other factors (often called 'promoters') work with somatic mutation to cause tumors: examples are irritants that lead to cell proliferation that could make cells vulnerable to mutation. That's one idea of why colon polyps may predispose to colon cancer.

Since every cell division leads to mutations in genome, every organism is loaded with cells that have slightly different genotypes from what the individual inherited. Recent papers have confirmed this idea and suggested that large numbers, even thousands, of somatic mutational changes may be involved in cancer 'transformation'. So an injury may simply give an advantage to cells that are mutated to be hyper-responsive to the blow and then spin out of control.

Paradigm shift?
This won't be a real paradigm shift in the proper sense of a truly transforming change in ideas, like Darwin vs creationism was. If trauma is just a trigger that gives environmental advantage to mutant cells, it won't even be a change in current thinking. But if the injury is inducing genetically normal cells to misperceive their environment, this would be a change in our understanding of the proximate nature of cancer (which has been that it takes abnormal genotypes leading cells to misbehave). Even then, it would not change our understanding of cancer as errors in cellular signaling and response, and hence in local cellular 'environment.'

So this is an interesting article and stimulates thought about the nature of an important class of diseases, and the continuity of life-processes from the cell-to-cell, to the organism-to-organism and on up, as they evolve in response to each other. Avoiding mutagens may not be enough to avoid cancer. 'Promotors' may be enough. But it is a lesson not in paradigm shifts but in understanding the ultimate cause of cancer, rather than its proximal or immediate mechanisms.

2 comments:

James said...

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Anne Buchanan said...

Yes, cancer can be a terrible disease. Do take care.