Cancer: Peto's Paradox • Cats 'N Lab Coats

I’m going to create a new series all about what I’m studying: cancer. I wrote an introductory post about cancer awhile back (I think it may have been my very first post) that was a broad explanation about cancer. With this series (creatively entitled “Cancer”), I want to dive deeper into it and address some of the controversy that might be out there.

To kick things off, I want to talk about something called Peto’s Paradox. This is an interesting phenomenon in cancer, and if we were ever able to fully understand what drives it we would be well on our way to preventing cancer.

Before I delve into this concept, let’s go back quickly and review some basics in case you don’t want to read my entire post about it (though it’s pretty good!). Cancer is a genetic disease and is determined by what happens to your DNA. DNA is in control of the cell – it dictates what type of cell it is, what proteins are made, when to grow and when to divide and create new cells, etc. When this DNA is damaged or mutated, it causes the cell to become uncontrollable. Uncontrolled growth is one of the hallmarks of cancer and is a driver of tumor growth. That’s all a tumor is – a mass of cells that were never told to stop dividing. However, the good news is that only one instance of damage or one mutation doesn’t trigger cancer development. It requires an accumulation – often a lifetime of accumulation – before the onset of cancer. Naturally, cancer risk increases as you age simply because you accumulate more of this damage.

Now let’s think about size as a factor in cancer risk. The bigger an organism, the more cells it has. Logic would dictate that the more cells present, the higher the cancer risk, since there are more chances for these mutations to occur and accumulate faster. This assumption has been proven to be false, thereby creating Peto’s Paradox. Simply put, there is no correlation between body size and lifetime cancer risk.

Here’s an easy way to picture this concept. Humans are approximately 1,000 times bigger (scientifically put, three orders of magnitude) than a mouse. Yet mice can have an astonishing 90% (depending on the mouse species) cancer mortality rate (meaning how many die of cancer) while humans have a cancer mortality rate of about 24%, depending on where you get the information from. In turn, a blue whale is approximately 1,000 times bigger than a human. If cancer risk were associate with body size, all blue whales would eventually develop cancer, yet cancer is a rare phenomenon in whales.

As an added point of intrigue, Peto’s Paradox only applies species to species. When looking within the same species, cancer risk is found to correlate with body size. I’ll use dogs as an easy example – a Chihuahua’s cancer risk is lower than a Greyhound’s risk, but dogs as a species have a lower cancer risk than mice as a species, if that makes sense. This is found to be true in humans as well, that people with larger bodies (whether it be weight or height or whatever) have a slightly higher risk of cancer. Of course, that risk varies from individual to individual based on genetics and diet and environment and a whole slew of other factors we won’t get into, so if you’re really tall don’t start worrying just yet.

The question remains, why is this true? How do larger organisms control DNA damage or inherent risk factors? If we could definitively answer this question, we could start developing preventative cancer therapies for individuals who have a higher risk for cancer. However, as with anything in cancer research, it’s extremely complicated and there likely isn’t one true answer. I want to lay out some of the concepts scientists believe contribute towards this cancer resistance in larger species.

Let’s go back quickly to thinking about what a tumor is. A tumor is a large mass of cells that don’t know when to stop dividing. The checkpoints that are in place for normal cells have either stopped working or are simply being ignored. One of these checkpoints is a signal that tells a cell when it’s touching another cell – a concept called contact inhibition. Cancerous cells ignore this signal and keep on growing no matter how many cells it touches. This phenomenon can be seen easily when growing cells in culture, as normal cells will grow in one layer (creatively referred to as a monolayer), but with “transformed” cells (cancer cells), they’ll start growing on top of each other too, essentially creating a tumor in a dish. Loss of contact inhibition is an important hallmark in cancer. One thought behind Peto’s Paradox is that these larger organisms have early onset of contact inhibition, so cells don’t even have a chance to get close to one another, let alone touch and squash and grow into a teeming mass. (What is it about the words “teeming mass” that always make something seem disgusting?)

Other possible explanations of Peto’s Paradox circle around ideas like slower metabolic rates – which creates less buildup of reactive oxygen species that can lead to cancer – or an increase in the amount or efficiency of tumor suppressor genes or a decrease in number or efficiency of oncogenes. The balance between tumor suppressor genes and oncogenes is a major factor in cancer development, with tumor suppressors being preventative (as I’m sure you could have guessed) and oncogenes being conducive to cancer. Larger species may have more copies of important tumor suppressor genes, which then require more total mutations in these genes prior to cancer formation. In fact, this has been shown already in species like elephants and whales, so this is likely one of the factors affecting Peto’s Paradox.

(If you are confused by the tumor suppressors/oncogenes, you can read my first post on cancer which explains them in more detail!)

I won’t go into more details or we would be here forever. I just wanted to convey the idea that the concept behind Peto’s Paradox isn’t unsolvable, just that there are a lot of considerations before we fully understand it. Research into this area of cancer prevention is beginning to pick up steam now, so hopefully in the future we can have a better overall understanding of how we can prevent cancer in humans on a larger scale.

Peto’s Paradox is an interesting phenomenon in cancer. Personally, I think it has created a lot of questions when it was first discussed (some 40 years ago now) that remain unanswered. This is partly because for most of the last century, cancer research has focused a lot on treatment (and a little less so on detection, but still a main part). I’m not saying this is a bad thing, we’ve made some amazing strides in these areas. It’s almost unbelievable to me that some patients can undergo “chemotherapy” by taking a pill at home. When my mom was going through treatment (10 whole years ago now), I remember she had to go to the doctor’s office to get her chemotherapy in an IV drip. However, this progress has slowed down a bit, to the point where we’re really focusing on personalized medicines and understanding the intricacies of diagnosing symptoms. Treatments are taking the big ideas from the past century and now refining them.

I think it is time to answer some of those questions raised by Peto 40+ years ago. It is time to fund more projects and invest in ideas surrounding cancer prevention, to study those animals that don’t develop cancer and really understand why. I truly believe this could be the next big step in cancer therapies – preventing cancer entirely.

Further/extra reading for those interested (some of these are linked above too):