Between Bedside and Bench

BEdsIdE TO BEnCh

Aspiring to prevent colon cancer

Patrick H Maxwell
Cancer of the colon and rectum is common, and, unfortunately, many affected people die from the disease. It is estimated that there will have been 141,210 new cases in the US in 2011. If identified early, colorectal cancer can be cured through surgical resection of the tumor. But, all too often, by the time a colorectal cancer is discovered it has already invaded through the wall of the bowel or metastasized to the liver. Modern approaches that combine surgery and anticancer drugs such as 5-fluouracil, cetuximab, irionotecan and oxaliplatin will cure some of these people and extend the lives of others. Yet in the US in 2011 there will still have been about 50,000 deaths from the disease. One approach to combat the disease is to detect it before it causes any symptoms by screening approaches that aim to detect precancerous polyps and early cancers. But this process is expensive and has limited effectiveness at a population level. For over twenty years, evidence has been accumulating that nonsteroidal anti-inflammatory drugs might provide a way of preventing colorectal cancer1,2. Now, two recent studies in humans have provided compelling evidence that daily aspirin can reduce the risk of developing colorectal cancer and dying from the disease. A long-term follow-up study investigated the use of aspirin for prevention of cardiovascular disease in four randomized trials, which used a daily dose ranging from a full dose, 1,200 mg, to 30 mg and assessed aspirin course of treatment that lasted from 1 to 8.6 years3. The standard dose of aspirin as a painkiller or antipyretic is 300900 mg, four times a day, with a maximum recommended daily dose of 4 g. The investigators used a robust approach to examine how many cancers and cancer deaths have occurred after the termination of these studies. Mortality due to colon cancer was reduced by about 30% over 20 years. Whereas 75 mg a day seemed to be as effective as larger doses of aspirin, 30 mg was less effective3. As expected, taking aspirin for longer periods of time increased the benefit. What is fascinating about these results is that the reduction was only evident after a latent period of about 7 yearseven after only 2 years of aspirin treatPatrick H. Maxwell is Dean of the Faculty of Medical Sciences, University College London, London, UK. e-mail: p.maxwell@ucl.ac.uk

Healthy intestinal crypt

? Aspirin

Dysplastic crypt

Myeloid cell ?

? Fibroblast ? ? Stem cell ? COX2 (Induced cell death or differentiation of stem cells with mutations)

2012 Nature America, Inc. All rights reserved.

Inflammation

Figure 1 Potential mechanisms of action of aspirin to prevent colorectal cancer. Two years of aspirin treatment can reduce the risk of developing colorectal cancer in individuals with Lynch syndrome several years after treatment. Although how aspirin acts to prevent cancer progression is still unknown, one hypothesis points at the targeting of intestinal stem cells, thus acting very early on in the path toward malignancy. But aspirin may also have a chemoprevention effect by acting on other host cells or the gut microbiota. Further investigation will be needed to fully understand how aspirin can prevent colorectal cancer in predisposed individuals and the clinical value of this treatment in other populations. Red nuclei indicate the presence of a mutation.

ment and several years with lack of treatment. Several years ago a study was conducted with 900 individuals with Lynch syndrome, an inherited condition associated with a very high risk of colorectal cancer, who were treated with either 600 mg of aspirin a day or placebo to test whether this would reduce the risk of adenomas and cancers4. When the results of the study were reported in 2008, there was no evidence of a beneficial effect, which was disappointing. However, 3 years later, a longerterm follow-up study showed that the original 2 years of treatment resulted in about 5060% decrease in colorectal cancer risk after about 5 years5. These studies underscore the power of randomized trials and the additional information that can be obtained from longer-term follow-up studies. One key point from these two long-term follow-up studies3,5 is the potential for drugs to be repurposed. Aspirin was developed over a hundred years ago as an analgesic; since then it has been shown to be also an extremely effective antiplatelet agent6. And now it seems promising for cancer chemoprevention.

Hopefully, there are many other medicines with similar untapped potential. In addition, these two studies emphasize the relevance of a stratified medicine approachan important concept in modern therapeutics where the aim is to identify a group of patients for whom the balance between benefit and risk or cost tips dramatically toward the benefit. In Lynch syndrome, for instance, genetic information might allow medical scientists and doctors to treat with aspirin a selected group for which the drug is especially beneficial. Nevertheless, a clinical question remains: identifying the optimal dose of aspirin. A related health economics concern is weighing the risks, costs and benefits of aspirin for different segments of the population7. On the one hand, it is clearly established that aspirin is very useful in people with cardiovascular disease8. But on the other hand, it increases the risk of bleeding, which usually affects the gastrointestinal or genitourinary tracts. Perhaps surprisingly, for the general populationespecially younger peoplethe risk of colon cancer is probably so low that the

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Between Bedside and Bench

potential harm of taking an aspirin a day to reduce the risk is not worthwhile. At the bench, a real challenge is to understand how aspirin reduces the risk of colorectal cancer. A crucial clue may be that the effect becomes evident only several years later. The delay implies that the effect might be happening very early on in the evolution from normal cells to a cancer; unfortunately, our current knowledge of the very first steps on the road to colorectal cancer is rather sketchy9. In contrast, we better understand how cells in the normal colon turn over. The colon has a very large number of crypts, with stem cells at their bases that provide a continuous supply of daughter cells that are pushed upward and differentiate in the process9. One appealing idea is that cancer may arise from the intestinal stem cells. A lead hypothesis would be that aspirin may reduce the population of intestinal stem cells across the colon that are one step down the road to cancer (Fig. 1). For instance, aspirin could push stem cells that have acquired genetic damage toward death or tip them toward terminal differentiation. Alternatively, aspirin could alter the dynamics of the crypts so that stem cells either are less likely to acquire genetic damage or are more stable from an epigenetic perspective. Mechanistically, it is probably reasonable to assume that aspirin may act by inhibiting cyclooxygenase II (COX-2), an inducible enzyme largely responsible for mediating inflammation, in the cells that give rise to colorectal cancer. Indeed, extensive animal data support a role for COX2 in intestinal polyp formation1. But scientists need to challenge assumptionsit is conceivable that the effect of aspirin could be via an effect on the microorganisms contained in the lumen of the colon or on some other cell type in the colon, such as fibroblasts or immune cells (Fig. 1). If the target is epithelial COX2, then it will be interesting to elucidate which of the many prostanoids produced downstream of COX2 are contributing. Existing experimental evidence would support a tumor-promoting role for the prostanoid prostaglandin E2 (ref. 10). One of the great pleasures in science is making unexpected connections. The inspiration for aspirin was the salicylic acid obtained from willow bark, which was a well-known plant remedy. It is attractive to speculate that there could be a link between the reason plants make salicylic acid (perhaps as a defense against pathogens11), the yet unknown mechanism by which aspirin reduces colorectal cancer and the fact that eating fruit and vegetables reduces the risk of colorectal cancer12. Scientific efforts should be focused on understanding how aspirin can reduce the incidence of colorectal cancer. Once we understand the mechanism of action of aspirin, it will provide a fundamental insight into how colorectal cancer develops and will allow targeted treatment for those who will benefit the most.
COMPETING FINANCIAL INTERESTS The author declares competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/.
1. Oshima, M. et al. Cell 87, 803809 (1996). 2. Thun, M.J., Namboodiri, M.M. & Heath, C.W. Jr. N. Engl. J. Med. 325, 15931596 (1991). 3. Rothwell, P.M. et al. Lancet 377, 3141 (2011). 4. Burn, J. et al. N. Engl. J. Med. 359, 25672578 (2008). 5. Burn, J. et al. Lancet published online, doi:10.1016/ S0140-6736(11)61049-0 (28 October 2011). 6. Yeomans, N.D. J. Gastroenterol. Hepatol. 26, 426431 (2011). 7. Cuzick, J. et al. Lancet Oncol. 10, 501507 (2009). 8. Baigent, C. et al. Lancet 373, 18491860 (2009). 9. Medema, J.P. & Vermeulen, L. Nature 474, 318326 (2011). 10. Wang, D. & Dubois, R.N. Oncogene 29, 781788 (2010). 11. Duthie, G.G. & Wood, A.D. Food Funct. 2, 515520 (2011). 12. Aune, D. et al. Gastroenterology 141, 106118 (2011).

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