One of the topics that most people find interesting is cancer. This is also true from an evolutionary perspective: what possible purpose could cancer serve? Is it just our bodies wearing out? Why haven’t we been able to evolve into a cancer-free species by now?
Those are great questions, and they’re ones that don’t really have great answers. I came across this article “Metabolic regulation of oxygen and redox homeostasis by p53: Lessons from evolutionary biology?” in my dermatology research. We’re often evaluating ways to reduce cellular stress (oxidative stress). My hope is that this review article gives us some good ideas about why we have cancer issues, from an evolutionary perspective–that’s what the title seems to imply.
What do you need to know before starting?
p53
p53 is a tumour suppressor protein. Its primary job is generally to monitor DNA for damage, and if there is damage, to stop the cells from dividing (and making more bad copies).
Oxygen
Oxygen is an element on the periodic table, and it usually runs around as O2 (two atoms of oxygen joined together). We need it to live. In fact, it’s important at the end of glucose metabolism: if you remember, that went something like glycolysis → Krebs cycle → electron transport chain → oxygen → carbon dioxide. Remember that glycolysis occurs in the cytoplasm, while everything from Krebs onward occurs in the mitochondria. Oxygen absorbs spent, energy-depleted electrons that you generate while breaking down glucose. There’s a relatively good video on this:
Although you’re no longer a fetus, the process is the same in adults. It’s good enough for now.
Redox Reactions
“Reduction-oxidation (or redox) reactions are at the core of our metabolic machinery. Redox reactions involve the transfer of electrons or hydrogen atoms from one reactant to another. (The process of taking away electrons is called “oxidation,” because oxygen does it so well. The substance receiving electrons becomes “reduced.”)”
From Am J Med vol 108 iss 8 pp 652-659.
“Occasionally, under normal biological conditions, oxygen does manage to steal away electrons from other molecules […] This breaking up […] results in free radical formation.”
From Am J Med vol 108 iss 8 pp 652-659.
Oxidative Stress
Free radicals create what we call oxidative stress, because most of the free radicals are oxygen-based. If oxygen picks up a single, really high-energy electron, it becomes a free radical. Cellular respiration (burning glucose, your normal metabolism) generates free radicals, too. These come in many flavors, and the nastiest is superoxide (·O2-). Superoxide can damage your DNA, proteins, lipids (like your cell membrane phospholipids) and other stuff inside your cells–so it’s dangerous. Your cells have antioxidants (such as vitamins C and E) that help to safely absorb these types of free radicals. In addition, an enzyme called superoxide dismutase (SOD) can combine superoxides to make good old hydrogen peroxide (H2O2, that stuff you buy at the pharmacy). Peroxide is still dangerous, but it’s not a free radical. You have two other pathways to get rid of peroxide: GSH and catalase (CAT). Ultimately, you use more oxygen to get rid of the superoxide and make water and safe oxygen. There are other types of free radicals, but this is the most common stuff.
Links with Cancer & Aging
A lot of research suggests that oxidative stress can promote cancer development and aging, but there is debate on that, too (you may want to take a side trip over to the Anti-Aging University Videos on Aging if you’re interested in aging; just remember to come back).
Some articles are starting to suggest that some oxidative stress is beneficial (like training for a marathon, your body is better prepared), and radical production is also tied to immune system function (you want to kill the pathogens, right?). This isn’t a totally black-and-white issue.
In general, though, much research supports a role for oxidative stress in promoting cancer. Cancer needs lots of energy, and needs LOTS of oxygen–so much so that you often grow new blood vessels to support the tumour (that’s called angiogenesis, and it’s one of the hallmarks of cancer). However, there’s still a lot of debate about whether oxygen itself is pro-tumour or anti-tumour.
Image from Cell vol 144 iss 5 pp 646-674
Mutations in the gene for p53 are particularly common in cancers. If this tumour suppressor gene is mutated and nonfunctional, the chances of cancer go up. We find this gene (well, eerily similar genes) even in single-celled organisms, which is bizarre because they can’t form tumours. Doesn’t that suggest that the gene may not be just for cancer? Other research has shown that p53 can affect multiple cellular pathways, including
On to the article…
Part 1: Oxygen toxicity and tumorigenesis
How is oxygen related to tumours? From above, you know that oxidative stress can damage DNA (including genes like p53), which can lead to cancer development. Researchers looked for other supporting evidence. Refer to Fig. 1 here: they found that people who lived at higher altitudes had lower rates of cancer. Another group did some experiments with mice who had no functional copies of the p53 gene and showed that when oxygen levels decreased, so did cancer rates. Additional studies showed similar results for an intestinal cancer model. Some of the evidence showed higher blood levels of antioxidants when there was less oxygen around; that makes sense, since less oxygen should mean fewer free radicals and fewer free radicals should mean that fewer antioxidants get “used up.”
Screen clipping taken: 8/30/2012 1:58 PM
Part 2: p53 and mitochondria are oxygen-responsive
We actually have a bunch of genes that are triggered by low oxygen concentrations. These are called hypoxia-inducible factors (usually abbreviated HIF, such as in HIF-1α ). That mitochondria are oxygen-responsive is kind of obvious: that’s where the oxygen is used. Duh!
So, is p53 one of those oxygen-responsive genes? It appears to be. Fig. 2 shows an overview of how p53 can be regulated. Lines with arrows indicate increased expression of a gene, while blunt ends indicate suppression. Based on this, low levels of oxygen trigger HIF genes, which help stabilize p53, allowing it to do its anti-tumour thing. High levels of oxygen increase other genes that increase p53 expression. That means that both low and high levels of oxygen appear to increase p53. Wait, what? How can that work? The outcome seems to depend on how much p53 you have. If it’s essentially normal levels of p53, you get antioxidants and normal cell metabolism. If you get too much p53 (due from either too much or too little oxygen), you get cell death. Oops.
Part 3: Redox regulation of p53
The next figure, Fig. 3, addresses what p53 does under normal circumstances. According to this figure, normal levels of p53 increase expression of several anti-oxidant genes (including CAT, which was mentioned earlier!). It promotes normal mitochondrial respiration, which should mean increased production of free radicals. It also promotes the pentose phosphate pathway (which is kind of an alternative to glycolysis) and inhibits glycolysis itself. Overall, this should control and prevent the production of excessive free radicals, while providing plenty of antioxidant “sponges” to soak up the ones that are made. The net effect is to block or inhibit oxidative stress, which reduces DNA damage & tumour formation.
Part 4: p53 can regulate redox homeostasis through the mitochondrion
What happens under conditions of high stress? Different genes are activated. Look at these results in Fig. 4 compared to the ones from Fig. 3 and you’ll notice that it’s a totally different set of genes, and that the effects are actually kind of reversed, too. Under high stress, p53 shuts down the pentose phosphate pathway. Some of the genes stimulate mitochondrial metabolism, but a few inhibit it. This appears to be a complete contradiction! If the damage is repairable, it may be beneficial to turn down metabolism for a while during repairs. If not, then p53 seems to accelerate the damage with the specific intent of killing the cell off (better a dead cell than a cancer cell!).
Part 5: p53 regulates oxidative stress via non-mitochondrial pathways
p53 has also shown the ability to turn expression of CAT and SOD up or down, depending on the levels of stress in the cell. These enzymes work pretty much all over the cell (in the cytoplasm). Previously, we noted that p53 turned down glycolysis under high stress. Glycolysis is anaerobic metabolism–it doesn’t require oxygen and doesn’t use the mitochondria–so we know that p53 affects the cell in an all-over fashion.
SUMMARY and ANALYSIS
Okay. This is where we start addressing some of the evolutionary questions. Based on what we’ve seen so far, too much (or too little) oxygen is bad, and can lead to oxidative stress. Oxidative stress can lead to damage, which in turn can lead to cancer. p53 appears to be responsive to oxygen, and seems to stop oxidative stress in one of two ways: by subtly altering metabolism (influencing production of antioxidants & aerobic metabolism under mild stress), or killing the cell (if the stress and damage are severe).
But has it evolved that way?
- Is p53 inherited? YES. We have identified the gene. It doesn’t get any more clear than that.
- Does p53 vary? YES. Expression of p53, in this case, was partially dependent on oxygen levels–and so were the target genes that p53 activates under normal or extreme stress.
- Does p53 affect survival or reproductive success? Since tumours tend to be widely accepted as bad, and cancer is one of the leading causes of death, I would say that yes, p53 is a gene that can affect survival. By killing off some of the worst-damaged cells, we improve the overall health of the organism. That is pro-survival, so it should be a preferred trait. Also, since p53-like genes are found so extensively throughout life, that tends to imply that this is a very, very important gene! “Consistent with the above findings, mouse and human cells lacking p53 show increased sensitivity to oxidative and nitrosative stress.”
Together, satisfying the criteria indicate that it is plausible that this system evolved as a way of regulating oxidative damage. But what about single-celled organisms? They can’t form tumours! No, they can’t, but reducing oxidative stress and DNA damage still means that your cellular body continues to function better–and prevents the really screwed-up single cells from reproducing.