Start taking daily aspirin? Buy stock in Bayer?

An aspirin a day...
Last week we blogged about the possibility that many chronic diseases have an infectious origin. Cancers, heart disease, diabetes, asthma and so on rather than having a genetic cause, as the unlimited funding stream supporting the hunt for genes 'for' these diseases suggests, might be infectious instead.  It wouldn't be the first time that an unexpected infectious origin was found for a common disease -- stomach ulcers were thought to be due to stress for decades, and the suggestion that they might instead have a bacterial etiology was laughed out of court.  Until it was conclusively demonstrated to be the case.

Several studies now have suggested that aspirin taken daily in low doses might protect against some of the most common cancers, or prevent its recurrence, including a study just published in JNCI, the Journal of the National Cancer Institute, described in The Guardian here. Researchers pooled the results of a variety of clinical trials of aspirin as a preventive for vascular events -- stroke and heart attack, and found a significant reduction in cancer mortality.  The relative risk  in this sample of 100,000 people for those taking a daily low dose of aspirin for up to 11 years was 16% lower than in those not taking aspirin.  This was a smaller effect than that of previous studies -- e.g., a paper in The Lancet in March, one in a series of reports by the same author, reported that cancer mortality among people taking aspirin for at least 3 years was reduced by a quarter.

The latest results are still significant, but the benefit isn't nearly as clear-cut as earlier reports.  An editorial accompanying the paper in JNCI discusses the possible reasons for the differing results and concludes that the latest estimates are probably conservative.  How this will translate into clinical practice is yet to be determined.  There is some risk to a daily dose of aspirin, even if it's a low dose, because it is associated with internal bleeding.  So, as long as the size of the effect on cancer mortality is still uncertain doctors probably won't be recommending we all go on aspirin indefinitely. 

But how?
If it is true, though, what's the mechanism?  Aspirin is an NSAID, a non-steroidal anti-inflammatory drug, and its two major effects are to reduce inflammation and to inhibit blood clotting.  Some have suggested that platelets (blood clotting factors) are associated with cancer, but we explore the inflammation angle here instead because that lead seems more solid.  If tumors are infectious in origin, reducing inflammation could conceivably reduce the tumor.  A report in the May Current Biology, by Yi Feng et al., does suggest a link between cancer and inflammation, but the inflammation appears to be intrinsic to the tumor itself rather than due to an external infectious cause. 

An association between the COX2-PGE₂ pathway and cancer progression is well-established (COX2 is a gene that regulates one of the prostaglandins, a hormonelike molecule involved in a diverse set of physiological processes such as uterine contraction and regulation of body temperature). COX2 is also associated with inflammation and pain, which is why so many pain relievers, including aspirin, are COX2 inhibitors.  It is known that COX-2 is expressed in the initial stages of tumorgenesis by malignant epithelial cells as well as other associated cells including macrophages, a component of the immune system.

Previous work by Feng et al. showed that innate immune cells were involved in the earliest stages of tumor proliferation.  They now have shown that PGE₂ is the signal that is responsible for this.  They further show that blocking PGE₂ synthesis by inhibiting COX2 expression slows tumor expansion, and suggest that this may be how aspirin, as a COX2 inhibitor, functions to slow tumor growth. 

We have provided evidence here that a trophic inflammatory response is important for a transformed cell to grow at its inception and that PGE₂ produced by innate immune cells via the COX-2 pathway is a key trophic factor for optimal growth of transformed cells at the earliest stages of tumor progression. Moreover, this trophic inflammatory response can be suppressed by the inhibition of PGE₂ production via COX-2 inhibitors, which might explain why use of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce cancer incidence.

If further work confirms that aspirin inhibits tumor growth, and that the mechanism is as proposed by Feng and colleagues, this precludes the usual idea about cancer and inflammatory response.  Rather than infectious agents such as viruses or bacteria, the cells that initiate cancer in the first place are themselves inflammatory.

If that is the case, then cancer cells should show some mutations in inflammatory-related genes, that are not found in surrounding normal cells in the same person.  That would indicate that the evolution of a particular lineage of the person's cells included such mutation.  It allowed the cells to proliferate, eventually to the detriment of the person.

A kind of selection would prevent these variants from being in the germ line, because the embryo would develop misbehaving cells, and would die before ever being born.   This is not 'natural' selection of the usual Darwinian kind, which is about competition.  Instead, in the 'Mermaid's Tale' flavor, it is a failure of cooperation among developing cells within an individual.  But the effect is similar: it removes harmful variation.

Of course, this is a serendipitous finding if it holds up, because we did not evolve eating aspirin (that is, the same compound, in plants).  In the past, cancer got who cancer got.  Now, we may be able to counter-act this harmful somatic (body cell) evolution.

An aspirin a day keeps the doctor away?

A paper published online in The Lancet on Dec 5 reports that regular aspirin use for at least 5 years reduces the risk of cancer by 20% over 20 years.  It's particularly true for gastrointestinal tumors, with reduction in risk of other specific cancers of up to 40%.  Since lifetime risk of cancer is 40% in the developed world, aspirin use could have a significant effect on cancer morbidity and mortality.

Writing about this study, the BBC reports:

For individual cancers the reduction was about 40% for bowel cancer, 30% for lung cancer, 10% for prostate cancer and 60% for oesophageal cancer.

These results are from a meta-analysis of 3 large observational studies of approximately 25,000 adults in the UK, originally randomly assigned to daily aspirin or control (placebo, another antiplatelet agent or nothing) to assess the effects of aspirin on vascular events (heart attack or stroke) and followed for 4 - 20 years.  Each study collected statistics on deaths from cancer as well as cancer incidence.

The number of some cancers was too small to allow estimation of risk reduction, if it indeed occurred.  Although how cancer reduces risk is not actually known, it either reduces incidence or the rate of growth of the tumor, and animal studies showed this was "mediated at least in part by inhibition of the cyclo-oxygenase (COX) enzymes and reduced production of prostaglandins and other inflammatory mediators", according to the BBC. 

Now, these results are interesting, not least because they were found serendipitously, as the result of looking for the possible effect of a daily dose of salicylic acid (aspirin) on vascular events, via reduction of blood clotting.   And one or more of the investigators were following up on earlier findings (perhaps in the same study) that aspirin may be protective against colorectal cancer. Because environmental factors are correlated and highly variable, whether aspirin on its own would have persistent effects in changing lifestyle environments is an open question.  People who have taken aspirin may be different in many unmeasured ways from others.  But let's take this study as given.

The surprising thing is that this seems an out of the blue finding: why aspirin?  One possible explanation suggested by the investigator was that cancerous cells respond to aspirin by undergoing apoptosis -- cellular suicide.  Why normal cells would not do that as well is unclear, and whether there was any substantial evidence for the explanation (as opposed to just a guess), we can't say. However, by chance we were having dinner with a visiting cell biologist from South Africa, and he said this is likely the result of the much higher metabolic rate of tumor cells, so that the aspirin effect would affect normal cells as well, but a far lesser rate; that is, the aspirin effect isn't targeting the tumor cells specifically.  Aspirin may affect vascular tissue (small blood vessels) in ways that deprive the 'hungrier' tumor cells.

A more important point to us is that we're in the age in which our NIH and other global research supporters seem determined to turn every disease into a genetic disease.  Cancer does indeed seem to be a genetic disorder at the cell level--genes gone bad for some reason lead the cell to misbehave and grow out of normal control.  Though many different means to alter gene function or expression in cells may be involved, they seem largely  to occur somatically during life.  That means that cancer isn't mainly 'genetic' in the sense of its causal mutations being inherited by children from their parents.

Some cancer susceptibility certainly is inherited.  But the risk increases associated with most genes currently known to affect inherited cancer risk are far less than the 20-40% figures claimed in this aspirin study.  This means that cheap aspirin prevention would be worth many times what we would be able to do using genotypes in expensive high-tech approaches.  So why devote so much funding to search for 'cancer genes', rather than intensely figuring out what to do with the genetic variants that we know really do increase risk?  We hasten to add as a case in point that such progress is certainly being made in this direction in at least some instances, including the notorious BRCA1/2 genes associated with breast/ovarian cancer.

More importantly, if we concentrated on those clear-cut cancer risk genes, while we let aspirin prevention take its course for many other common tumors, we would be left with the cancer cases that are more likely to be really genetic -- the ones that occur despite taking aspirin.  Maybe that is where genetic research in cancer should go, rather than into huge, open ended black holes of long-term megagenomics projects.