The Bacterium Behind Colon Cancer

Today I wrote a post for BigThink that I've been meaning to write for weeks. In August, several papers were published showing that a particular bacterium, Fusobacterium nucleatum, is strongly implicated in development of colorectal cancer (CRC).

Fusobacterium living in intestinal mucosa.

The latest research in no way invalidates the huge existing body of work showing strong (almost certainly causal) connections between CRC and consumption of alcohol, sugar, meat, and/or tobacco. There are other risk factors as well, such as lack of physical activity (by itself), obesity,  and genetics. (See this paper and this one for more discussion, and by all means do further investigation on your own using Google Scholar.) Genetic susceptibility, however, plays a role in no more than about 5% of CRC cases. (And even in those cases, it's by no means certain that bad alleles constitute a death sentence.)

The picture that's emerging is a complex one in which intestinal dysbiosis triggered by (for example) poor eating habits leads to the differential accumulation of various species of gut bacteria (Bacteroides fragilis, Fusobacterium nucleatum, and others) that are implicated in colorectal cancer. At some point (over a period of years, apparently), Fusobacterium gains entry to intestinal muscosal cells. (F. nucleatum has aspects of an intracellular-parasitic lifestyle.) Once it has established residency, F. nucleatum overproduces FadA adhesin, a small protein containing 129 amino acids, the exact sequence for which (in FASTA format) is:

>tr|Q5I6B0|Q5I6B0_FUSNU Adhesion A OS=Fusobacterium nucleatum GN=fadA PE=1 SV=1
MKKFLLLAVLAVSASAFAATDAASLVGELQALDAEYQNLANQEEARFNEERAQADAARQA
LAQNEQVYNELSQRAQRLQAEANTRFYKSQYQELASKYEDALKKLEAEMEQQKAVISDFE
KIQALRAGN

The letters here correspond to amino acids, using the standard one-letter code system (as presented here). In three dimensions, the FadA protein looks something like this:

Your new worst enemy: FadA adhesin produced by Fusobacterium nucleatum, the "kickoff protein" for colon cancer.

When this relatively small protein binds with normal E-adhesin (in a specific 11-amino-acid region), it activates β-catenin signaling, which in turn unleashes a cascade of cytokines (cytokines IL-6, IL-10, IL-12, IL-17, plus TNF-α) and an inflammatory cycle that leads straight to adenoma of the colon.

For the non-paywalled research paper on this, go to http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0053653. Read that paper (and this one, if you can) and decide for yourself how strong the case is for F. nucleatum FadA as a causative agent in colorectal cancer. I think it's pretty clear. We're looking at a smoking gun.

Now the really interesting thing about F nucleatum is that it's most commonly found not in the large intestine but in your mouth. Which brings up some interesting questions, right? For example: How does poor oral hygiene correlate with colorectal cancer? Little work has been done on that specific connection, but a huge amount of work has been (and continues to be) done on the substantial and increasingly obvious link between periodontal disease and cancer in general (which I'll probably blog about at some future time).

If the link between F. nucleatum's FadA protein and CRC proves to be as solid as it's starting to look, it opens countless doors to new therapeutic approaches to CRC treatment and prevention. We need to know, for example, if specific probiotic treatments can greatly reduce the risk of precancerous adenomas by staving off dysbiosis. We also urgently need to know if the outlook for early-stage CRC patients can be improved with aggressive use of antibiotics, including antibiotic-induced near-sterilization of the large intestine followed by fecal transplantation to restore the normal flora.

It hardly needs mentioning, but if it turns out to be true that CRC is mainly a result of a single bacterium, perhaps a vaccine can be developed, either against Fusobacterium or against the FadA protein, or both.

I'm extremely encouraged by the recent research pinpointing FadA as the likely culprit in CRC. Obviously, much work remains to be done. But we have an exciting new insight into this particular type of carcinogenesis. The treatment options that come out of it may well lead to other cures.

Some of us (here I'm speaking with my microbiologist's hat on; I have an advanced degree in the subject) have long suspected that microbes play a role in fostering—and preventing—various cancers. When I was in graduate school, you could count the number of microbially caused neoplasms on your thumbs. Now you have to use most fingers of both hands. Who knows what the full truth may yet turn out to be?

Exciting times.

If you enjoyed this post, or the corresponding one at BigThink, do me a favor. Tweet it or share it in some fashion. This is knowledge that deserves to get out. Who knows? It may save a life.

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The Geography of Cancer

Yesterday I wrote about the geography of colorectal cancer (CRC) and showed a map of CRC mortality in the U.S. The striking thing about the map was (is) that CRC is much more of a problem in the northern states than in the southern states. It turns out this is not an anomaly and in no way limited to the U.S. Colorectal cancer tracks latitude, worldwide. The further you live from the equator, the greater your chances of dying of colorectal cancer.

The above graph comes from a 2005 paper by Mohr et al. that correlates cloud cover and distance from the equator with cancer rates in 175 countries. It shows quite clearly that colorectal cancer incidence varies with latitude. The countries with the lowest CRC rates are near zero degrees latitude (the equator).

This effect doesn't just apply to colorectal cancer, though. It also applies to breast cancer:

Breast cancer and colorectal cancer are distinctly different cancers, so in order for these graphs to be as similar as they are, there must be a common denominator of extremely broad applicability underlying the latitude trend. It turns out the common denominator is vitamin D.

I'll spare you the book-length treatment. Suffice it for now to say: More than 2,500 research studies have been published in biomedical journals investigating the inverse association between vitamin D, its metabolites, and cancer, including almost 300 epidemiological studies. For a good overview, I recommend the review article by Garland et al. (2009). You might notice (as I did) a certain amount of hesitancy on the part of big-name researchers to come right out and pronounce vitamin D a bonafide cancer-preventive agent, due to the relative dearth of prospective (intervention-based) randomized controlled trials. (One intervention study worth reading is the 2007 trial by Lappe et al. in Am J Clin Nutr.) After the CARET disaster, no one wants to get caught recommending a vitamin regimen based on epidemiological happy-talk, and I can understand that. Nevertheless, I think the weight of the evidence in favor of vitamin D, at this point, is substantial enough (and any down side negligible enough) that people should start thinking about taking substantial amounts of vitamin D as prophylaxis against cancers of all kinds (not just CRC and breast). My advice is: Read the literature and decide for yourself. Don't wait for FDA, CDC, the National Cancer Institute, or anyone else to give you the green light on this one. They've got their own agendas to worry about.

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Cancer Mortality: North versus South

Today's maps are again brought to you courtesy of http://ratecalc.cancer.gov/ratecalc/, where you can easily spend a lunch hour (and then some) becoming engrossed in epidemiological mysteries with no apparent answer.

You don't have to spend much time with cancer maps to convince yourself that cancers occur non-randomly with respect to geography. A good case in point is colorectal cancer (CRC), which appears to be mostly a disease of the northern latitudes, at least in the U.S.

Sure, CRC occurs in the southern states, too. But there's no denying the preferential buildup of mortality in the Northeast. Bear in mind these maps are population-corrected; they reflect death rates per 100,000 people. (In other words, red areas aren't simply high-population areas.)  I think it's interesting to note that CRC tends to track the Mississippi River (and perhaps the Hudson River as well). Don't ask me what it means.

When you look at liver cancer in men, you get more or less the inverse picture:

Evidently your chances of dying of liver cancer are best in the South. Why? Risk factors for liver cancer include gender (male), obesity, alcohol consumption, ethnicity (Asian), smoking, diabetes, use of steroids and certain other drugs, and exposure to aflatoxins (a type of toxin produced by fungus). Some of these factors (alcohol, obesity, diabetes, smoking) are correlated with poverty. Here's a map of poverty in the U.S. (also see the maps in my earlier post on poverty and obesity).

The conclusion isn't that poverty causes cancer. Poverty does, however, correlate with many of the things that lead to liver cancer. Obesity correlates very well with poverty (see my earlier post), and as it happens, obesity increases your odds of death from liver cancer by a factor of 4.5 (see this NEJM paper, p. 1630, for details).

As to why colorectal cancer mostly kills northerners: That's a bit of a mystery. Risk factors for colorectal cancer include alcohol, obesity, diabetes, smoking, animal fat (red meat diet), sugar consumption, inflammatory diseases of the bowel, sedentary lifestyle, and genetics. I don't think any of those things correlate with living in the Northeast. In fact, some of them (through poverty) actually correlate with living in the South. However, it's fairly well known that vitamin D is protective against many types of cancer and lack of sunshine is a risk factor for cancer.

There's actually a microbiological factor associated with CRC that's worth talking about in some detail (in a later post) that could, conceivably, relate to geography. More on that later.

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