Most stories start with the adventures of a hero, who goes on an adventure to discover his/her powers and how he/she can use them to save others. However, it would be misleading to start this story with a hero – instead, it begins with a monster.
Around 1600 BC, in the sandy land of the thriving ancient civilization of Egypt, a high priest and physician collects horrible stories of a parasitic monster – an uncontrollable mass that grows in people’s bodies and kills them. The attempts to control it (or kill it) are described but ultimately the final description is that it’s a disease for which there is no cure. These records, in Edwin Papyrus1, are considered the first medical description of cancer. Others had witnessed the devastating effects of cancer, but as the knowledge was much smaller than the fear, most records report it in a more mystical and superstitious way.
So it begins the tale of what cancer, this parasitic monster, really is.
Once upon a time…
In the inspiring Greek civilization, Hippocrates took it upon himself to study this beast. In the new form of logical thinking, away from magic and superstition, he looked at it and described it as crab or karkinoma (a term still used today to classify different types of cancer, p.e. carcinoma, adenocarcinoma). This crab, with a body from which legs would emerge and claws that would hold tight to its surroundings, was believed to originate from a loss of balance between the “Four Humours”: black bile, yellow bile, phlegm, and blood.
Claudius Gallen, a Greek physician took these findings to Rome, where he described that the parasitic monster would develop if black or yellow bile accumulated in a certain part of the body, and if it were black bile, there would be no cure. Much later, Aulus Cornelius Celsus translated Hippocrates’ word into Latin and carried on with the great task of trying to defeat the monster newly named cancer (a term that refers to the disease caused by a malignant tumour).
Fast forward to the present…
We have found that it’s not the accumulation of humours but of DNA mutations that cause cancer. More crucially, we have found that cancer is actually a collection of diseases caused by different types of tumours. Defeating one monster is hard enough, but discovering that they are actually different from each other means that there is no single cure to defeat it. The key to understanding this is to first understand how tumours are really formed, and how they become cancer.
How do normal cells become tumour cells?
This process is called tumorigenesis and is not completely understood. One of the main reasons why not, is because the process itself is multifactorial and extremely complex, let me explain to you how:
As mentioned before, we do know that it’s the accumulation of DNA mutations that causes cancer, in the actual sense, that it’s DNA mutations that originate tumour cells. Our DNA holds the information to generate all that we are by the expression of genes. As normal cells divide (process of proliferation), the DNA needs to be replicated each time, and every time there is a tight regulatory process that makes sure that the DNA doesn’t suffer changes. To help with this process there are genes and proteins that form the DNA damage repair machinery. These are specific genes and proteins that monitor if there are any errors during DNA replication and if so they trigger a repair or induced-death mechanism, to prevent that cell from “spreading the wrong DNA”.
The mutations in our DNA are naturally occurring and our machinery is highly efficient at detecting them and correcting them. However, some may slip through (for example, our skin moles), especially if cells are dividing too fast for the system to keep up with all the errors, and also, particularly damaging when the mutation occurs in a critical gene of the DNA repair machinery.
There is another team, our immune system, made of cells and protein complexes that’s responsible for constantly checking, detecting and eliminating threats (foreign – like viruses or bacteria – and domestic – like tumour cells- a little pun from the FBI).
When DNA replication is unchecked and originating mutations, it creates what we call DNA instability, the source of tumour cells. Tumour cells are abnormal cells, meaning, that their communication pathways (cell signaling pathways) and cell functions are altered. However, these cells are considered benign when whatever makes them abnormal is still relatively regulated. It takes different types of mutations, that impact certain cell functions in a particular “advantageous” way for these cells to become malignant (and therefore, causing cancer). Specifically, these cells need to acquire mutations that allow them:
- to proliferate constantly
- to avoid anti-proliferation control
- to become immortal
- to avoid death-inducing mechanisms
- to generate new blood vessels that support that continuous growth
- to migrate and invade other tissues
- to avoid immune system mediated destruction
- to adapt metabolically
To summarize the process, imagine a cell that suffers a mutation in a critical gene which allows this cell to survive with a DNA mutation. This cell proliferates, and the daughter cell will also have this advantage, to survive, but will also accumulate new DNA mutations, because the system isn’t working as it should. Then these two cells proliferate and pass on again this advantage and more mutations are accumulated. All these mutations are random, but when they affect genes linked to any of the cell functions mentioned above, it gives them a survival advantage over their environment. This accumulation of slightly different cells, with different levels of mutation and advantages, is what creates a tumour mass, and as it continues to grow and eventually spread, is what creates the disease (cancer).
It’s because it seems like these cells become competitive against their neighboring cells, that I chose to refer to them as a parasitic monster, because much like a parasite, a malignant tumour becomes different and toxic to the body, while it does its best to drain out any resources of energy, even if it kills the host.
So how do we kill it or how do we prevent it?
Prevention is key, just as avoiding eating parasite eggs, not having it to begin with is the main idea. The main causes of DNA instability, apart from inherited DNA mutations, are within our control to a point. They can be summarized as environment and inflammation. There are many environmental factors that cause higher rates of DNA mutation (carcinogens), which then makes it more likely that our machinery won’t detect them all. Exposure to UV light, tobacco, alcohol, and other chemicals in cosmetics, medications, food and air are considered carcinogens, and avoiding them or reducing exposure to them is a great way of preventing cancer. Inflammation is more complex than carcinogens. Inflammation is a natural, internal process that occurs when our immune system is repairing or fighting some threat. However, this process is only healthy when it’s short-lived. When we are exposed to long-term inflammation (chronic inflammation), there is a greater dysregulation of natural cell communication pathways. This is because inflammation is a coordinated event that needs to override certain communication channels, and when it does this for too long, it destabilizes the underlying ones, like an army overrunning your hometown. Certain foods, stress, poor sleep and diseases cause chronic states of inflammation, so reducing it would help preventing tumour formation. Also, many types of cancer are associated with infections by viruses or bacteria, this is why overall hygiene and access to vaccines is extremely helpful in preventing certain cancers. One of the biggest accomplishments of late was the success in developing a vaccine against different strains of the papillomavirus, which is the main cause of cervical cancer.
Finally, the big question: How to kill it? Well, since we’ve learned that this parasitic monster is actually different kinds of monsters, in which each cancer is constituted by a tumour mass, that is in turn constituted by different cells with slightly different types of mutations, it’s only understandable that to kill it we need different strategies. Find which they are in the next post.
- Edwin Papyrus, “The Art of Medicine in Ancient Egypt” by James P. Allen (2005).