Misconceptions about cancer and Alzheimer's disease

emember the old days when we were solemnly informed daily that this or that chemical caused cancer? The joke was that laboratory mice caused cancer. There is new research that suggests that cancer and Alzheimer's disease may be two sides of the same coin. That means that cancer biochemistry has now suddenly become interesting to neuroscientists.

It turns out there are an amazing number of misconceptions about cancer. Many fact-checking sites like to pretend that it's easy to classify a statement as either true or false. But science is not so simple. Some of the examples below are from The Biology of Cancer, second edition, by RA Weinberg (2014).

Misleading fact: Red meat causes cancer

Red meat is near the top of the list because of the supposed link between cows and global warming. The idea was that heterocyclic amines such as PhIP, aka 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine, which are formed by cooking meat at high temperatures, can change G nucleotides to T and delete G from GGG sequences found in some p53 alleles in colon cancer cells.

Cancer cells

We now know that PhIP is also formed by cooking fish and many other foods. We don't hear much about that from the press, and so far there seems to be no proof that heterocyclic amines are even the culprit. More recent thinking is that intestinal bacteria are actually responsible. Stomach cancer in the USA has declined by a factor of six over the past 75 years due to better food storage that prevents fungal contamination. So maybe we shouldn't rule out fungus either.

The general idea nowadays seems to be that anything that gets burnt causes cancer, whether it's sunburn, diesel fumes, cigarettes, beef, or burnt toast. The question of whether there's some toxin in the burnt food, or your intestinal bacteria are manufacturing a toxin, or something else is happening, is under debate and needs more research.

It takes five or six hits to an individual cell's DNA to turn it cancerous. Those hits have to be in specific points, so the probability of any somatic DNA mutation being cancerous is infinitesimal. These hits are so infrequent that each one occurs on average once every ten to fifteen years. That's why most—but not all—cancers are strongly correlated with age, and it's also why if every cancer were prevented tomorrow it would only increase our average lifespan by 3.83 years for men and 3.38 years for women.

(This is a slightly misleading statistic since only 22% of all deaths are attributed to cancer. For those who would be cured, the increase would be much greater.)

Cancer researchers have essentially converged on mitosis as the focus of cancer. Mitosis (cell division) is very risky for a cell: if there is any problem with the DNA, the cell could die. The most dangerous mutations are those that affect proteins that control whether mitosis can start, such as p53 and pRb. This in turn depends on whether the cell detects DNA damage, so mutations in proteins involved in DNA repair, such as MDM2 and BRCA1 and 2, are also important.

Oversimplified fact: Alcohol is a tumor promoter

Ethanol was originally thought to be a tumor promoter due to its ability to cause cell death, forcing cells to undergo mitosis to replace them. More recently it was thought that acetaldehyde, a metab­olite of ethanol, rather than ethanol itself, caused DNA mutations which led to cancer. However, disulfiram (Antabuse), which inhibits acetaldehyde oxidation and thereby increases its concentration, not only does not cause cancer, but is now being tested as an anti-cancer agent, possibly by inducing cell death. Sometimes science just goes around in circles and ends up where it started.

Unprovable speculation: Racism causes cancer

It's well accepted that darkly pigmented people are much less likely to get skin cancer. The idea about racism is that it causes stress, which causes people to eat more high-calorie food, which makes them obese. And indeed, obesity or high BMI statistically increases the risk of certain cancers. For example, in males with BMI over 3.4, the risk of liver cancer is increased by 4.5 fold and for females kidney and uterine cancer are increased by 4.8 and 6.3 fold respectively. So what's really happening is that obesity is correlated with cancer. The rest of it is pure speculation.

How might obesity cause cancer? One early theory was that hyperinsulinemia, or high levels of circulating insulin, increases the level of insulin growth factor 1 (IGF-1) and reduces the levels of IGF binding protein. IGF-1 protects cells from apoptosis (programmed cell death), the theory went, so if a cell got mutated it would keep growing instead of undergoing apoptosis as it was supposed to.

The new theory is inflammation, and the new villain here once again is intestinal bacteria. So we're getting flooded with reports claiming that any kind of inflammation causes cancer, including LPS, which is a fat-sugar molecule produced by bacteria. LPS is very good at producing inflammation, and inflammation produces reactive oxygens such as hydrogen peroxide, which cause DNA damage.

Inflammation is a natural response to foreign molecules including cancer cells. So the conclusion must also be that cancer causes cancer. We've eliminated the middle man—mice are no longer needed.

The idea that racism causes any of this is not only unparsimonious, it is unfalsifiable and unprovable. How would you design an experiment to test it? You'd need to select a group of subjects and act racist toward them and see if they get cancer. Good luck getting an IRB to approve that.

Pesticides, not so much

Remember the hysteria from the 1970s about synthetic pesticides? It is now known that humans get 2 grams daily of burnt material from food (which puts you at risk) and 1.5 grams of naturally occurring pesticides made by plants, but only 0.1 mg of synthetic pesticides. Half of the naturally occurring pesticides register as carcinogenic in lab tests, as do half the synthetic pesticides. This raises doubt as to whether synthetic pesticides ever really caused many cancers.

There are three possibilities: (1) The tests were wrong; (2) Vegetables are bad for you; or (3) The quality of cancer research has improved. I'd say door no. 3 is the best bet, but 1 and 2 can't be ruled out. It's also a good idea to try not to burn your food. I have been told, for instance, that roast beef is not supposed to be black and crispy.

True: Cancer is transmissible in dogs

Everyone knows cancer is not contagious in humans. But it can be contagious in Tasmanian devils, vicious marsupials that often bite each other on the face. These animals can transmit cancerous cells to each other by biting. This causes tumors that prevent the animals from eating, so they die of starvation. Something similar happens in dogs, who transmit CTVS or canine transmissible venereal sarcoma, to each other when mating. These are cells that have lost their histocompatibility antigens, so they aren't recognized by the recipient as foreign and continue to grow. Luckily, after 3–4 months, the cells start expressing both MHC class I and II and the recipient starts rejecting the foreign cells.

Fact: Not everything is an oncogene

Years ago I developed a new anti-Alzheimer drug. It was chemically similar to DHA, which is a nutrient sold in health food stores, and it was promising: giving it to mice with traumatic brain injury practically cured them overnight. But thanks to the fad, now thankfully ended, of cancer researchers calling anything that induces cell repair an oncogene, you will never see it.

I submitted a grant for funding to do a preclinical study to test this new drug. The reviewers loved the grant but rejected it anyway because there were a handful of published papers that claimed—incorrectly—that our target protein was an oncogene. Without funding, the project had to be abandoned.

An oncogene is a gene that has a mutation that interferes with the protein's normal function and prevents the cell from controlling its mitosis cycle. It's vital for a cell to avoid going into mitosis whenever there's a problem with the chromosomal DNA. If it tries, the DNA can end up as a tangled mess. But sloppy science sinks ships. For a while, cancer researchers were calling everything an oncogene if eliminating it prevented a cancer cell from growing. The science has improved since then, and those claims disappeared from the literature, but by then I'd moved to academia. My former boss went with a different drug. Its advantage was that it had already been tested as an anti-cancer drug (where it had utterly failed), so oncologists couldn't shoot it down. Unfortunately, it also did nothing for the Alzheimer patients either.

Possible but unlikely: Traumatic brain injury causes cancer

Maybe the weirdest idea out there is that getting hit on the head causes cancer. There are a bunch of papers on this ^[1,2] but the researchers don't sound convinced. The hazards ratios are all over the map. Unfortunately, every article on the topic is paywalled.

That claim also conflicts with what we know about Alzheimer's. The evidence is very strong now that Alzheimer's disease, or AD, and cancer are to some extent mutually exclusive. The idea is that AD and cancer are in some ways opposites. Many of the same changes that occur in cancer also happen in AD. Both are accompanied by inflammation. Oxidative stress has long been known, and DNA damage is found in both diseases, as one Nature paper accidentally discovered. And the tumor suppressor protein p53 is through the roof in AD. But neurons are post-mitotic, so they never undergo mitosis, which means it's tough for them to get cancer. So, what happens to them?

The answer lies with p53, which gets activated by phosphorylation when there is an unrepairable double strand break in the DNA. p53 induces the expression of a protein called MDM2. The function of MDM2 is to get rid of p53 ubiquitinating it. Once ubiquitination starts, other proteins pile on and ubiquitinate it more, and p53 gets proteolyzed. If p53 gets phosphorylated, it stops interacting with MDM2. Cellular stress causes p53 to form tetramers, which can induce apoptosis and cell cycle arrest.

So, in effect, p53 induces a protein that will destroy p53 unless there is an unrepairable problem with the cell's chromosomal DNA. p53 is like the famous self-destruct button on the Starship Enterprise. Without p53 the cell merrily continues to undergo mitosis irrespective of the DNA damage. Sometimes the DNA gets hopelessly tangled up. How this causes Alzheimer's disease is still a mystery, but it was cancer research that discovered it.

Getting whacked on the head can cause inflammation. Some researchers are saying that just like LPS, anything that causes inflammation will act as a cancer promoter. But it's still a minority view.

False: Global warming causes cancer

Many of the articles on this one are where you'd expect: in The Lancet ^[3]. The idea seems to be that things that cause global warming also cause cancer. It's mostly handwaving about tobacco and meat production causing both cancer and global warming ^[4] but also that loss of biodiversity is somehow related to cancer. It's more activism than science: to encourage action on warming, activists tie it to something that everyone agrees is bad. Even so, there are two molecules in particular that have received attention from credible scientists: nitrogen dioxide and PM2.5.

Nitrogen dioxide, particulates, and cancer

Nitrogen dioxide (NO₂) is a toxic gas, not to be confused with nitric oxide (NO), which is produced in the body, or nitrous oxide (N₂O), which is found in racing cars. NO₂ is a radical, and it reacts very rapidly, forming nitrite and nitrate. It's also a strong oxidant, so it could in principle cause cancer. So far, most studies are statistical correlations among urban populations. They have been unable to separate NO₂ from the many other toxins and stresses in the urban environment.

One study ^[5] claimed that 15 parts per billion of NO₂ increased the incidence of breast cancer in premenopausal women by 13 percent but not postmenopausal women. This is a very weak association.

As for PM2.5, it is an irritant that causes lung inflammation^[6]. One theory is that this is what makes it dangerous.

Possibly true: Nitrogen dioxide and PM2.5 cause Alzheimer's disease

One study in Barcelona ^[7] claimed that exposure to green spaces (low noise, more vegetation) and low NO₂ protected against loss of gray matter as measured by MRI.

Loss of gray matter doesn't necessarily mean loss of neurons, even in elderly persons where it is well established that gray matter loss occurs. Most gray matter loss is due to shrinkage of neurons, reductions of the number of synaptic spines, fewer synapses, and shorter length of myelinated axons. If you get depressed, your gray matter decreases because you have fewer synaptic spines. Between 25 and 100% of the differences between young and old participants are due to these factors.^[8] Even the "cognitive reserve" idea is still only a hypothesis.^[9]

PM2.5 is a term for carbon-containing particles that are ≤2.5 microns in diameter, i.e. soot. The question we must ask about PM2.5 is: how in the world does such a big particle get into the brain? And if it does, could we use it to transport drugs into the brain—a holy grail that has eluded science since the blood-brain barrier was discovered?

It might not be necessary for those particles to actually reach the brain. For example, they could cause inflammation in the lung that releases cytokines that cause problems in the brain.

The idea of inhaled gases is appealing because the entorhinal cortex, where AD starts, is close to the nose. The explanation often given is that these substances induce inflammation. To evaluate these claims, we need to ask basic pharmacological questions: how does it get into the body, how much gets in, what concentrations reach the brain, and how long does it stay there?

Some researchers even speculate that COVID-19, which seems to affect the olfactory bulb, could be inducing an AD-like syndrome.

Conclusion

These studies have value in giving us clues to think about this puzzle, but it would be a mistake to jump up and claim that diesel fumes and nitrogen oxides contribute to AD. The news media report them because they love stories that encourage elimination of internal combustion vehicles. But when you read the phrase "air pollution has been associated with" something, it does not necessarily mean that a causal relation exists. More likely, as with so many other things, the relationship is very complex.

Eventually, when science has advanced far enough, it begins to approximate what we already know from common sense. But it's a long journey, and it takes boatloads of grant money to make that happen.

aug 02 2021, 5:48 am