All I didn’t know about Cancer

http://www.thinkingofthings.com/blog/cancer/

 

I wrote this a few years ago for a different context and purpose, while bored on a beach in Puerto Rico. The context and purpose were replaced many times over, and the text was forgotten. Now I was reminded of it and I dug it up to be posted here.

I do not remember how I came to realise that all I knew about cancer was wrong, but I remember discussing it with my friend the prostate cancer researcher, who gave me the articles (referred to at the end), which I was reading and writing about on that beach. Maybe I wasn’t that bored after all…

Here it is. 

Three of my grandparents died from cancer. One of them was treated with chemotherapy, one with surgery, and one with radiation therapy, all to no avail. These are the three main methods for treating cancer today. Chemotherapy was first used in its current form in 1942. A search for “cancer” on the online data base for medical publications, PubMed.gov, shows that 2.7 million scientific papers have been written on the subject since 19421. Still, the treatments remain the same, albeit more accurate, cheap, and accessible. For some cancers, like some leukaemia or testicular cancers the chemotherapy is highly efficient, while other diagnoses still come with “a few months up to a year” attached to them. So, in a way we are celebrating over 70 years of not improving cancer treatment much.

Why is that? Why has a cure for cancer not emerged in the course of those millions of publications? Well, cancer is a tricky beast and we are only recently beginning to learn how it works. We are also beginning to learn how cancer does not work (but we thought it did). Also, maybe more surprisingly, we are starting to learn why we do not get cancer (most of the time) and that a tumour is not necessarily a bad thing. Let’s start the story with how it does not work.

How cancer does not work (but I thought it did)

2It used to be believed that a cancer tumour started with a single mutation in a single cell, and that this mutation was due to free radicals produced in the metabolism of the cell, attacking the genetic material. Therefore, antioxidants, such as vitamins C and E, were believed to protect against cancer, since they react with free-radicals before they have time to harm the cell’s DNA. However, since this explanation was presented in 1961 it has failed to live up to the test. This is what the National Cancer Institute, a branch of the US Department of Health and Human Services, says about anti-oxidants’ ability to prevent cancer: “In recent years, large-scale, randomized clinical trials reached inconsistent conclusions”. Some anti-oxidants have been found to be cancerogenic themselves in large doses.

A completely different picture is emerging from numerous experiments, some of which I will describe here. Two examples: A cancer tumour does not always consist of similar cells; in fact, it is most often quite diverse, or ‘heterogeneous’. Also: In a region of the body where a tumour is found, more than one tumour is often found.

These examples do not seem to quite comply with the image of a cancer tumour being a single cell gone bad. There appears to be something else to it. As it turns out, the question is not only “Why do we get cancer?” but equally “Why don’t we get cancer, all the time?” Let’s take a detour through history to find out why that is an important question.

A detour through history

Once upon a time, a few billion years ago, the stinking goo that was life back then consisted only of single-cell organisms. These organisms were immersed together in different puddles of goo all over this little globe of ours. In a given puddle-o-goo, the different cells competed for the available nutrients, and the cells that were better at obtaining them were the ones that also became more numerous through the process of cell splitting. The competition was two-fold, it had a peaceful side where the cells competed at just being better at eating, and a non-peaceful side where the cells could kill competitors with poisons etc. The genes of the cells which were more efficient at eating vitamin-goo while fending off competitors, got the biggest spread in the population. When the cells reproduced through splitting into new cells, the new cells were not always a perfect copy of the parent cell, sometimes they were subject to random mutations, and sometimes these random mutations made the organism even better at obtaining vitamin-goo (most often it didn’t).

When things in the goo environment changed, for example the salt level of the goo could suddenly increase for some reason, the mutation rate in the cell-splittings increased. When everything is fine and unchanged, there is little difference between parent cell and baby cell, but when things change, the cells get annoyed, and the mutation rate increases, causing larger differences between the baby cell and its parent. This enables single cell organisms to adapt quicker when it is necessary. Since most mutations are harmful, there is an optimal mutation frequency for cells, which makes them able to adapt to the environment but not at the cost of too many harmful mutations. The mutation rate is dependent on the environment.

Mmmm... gooo... nomnom... Amoeba Eats Cells Alive, Spits out Corpses. From: Nature 508, 526–530 (24 April 2014)

Mmmm… gooo… nomnom… An amoeba eats cells and spits out their remains. From: Nature 508, 526–530 (24 April 2014)

You see, mutations are definitely not a byproduct of free radicals being released during the cells’ metabolism; they are a genetic feature–not a flaw. This feature enables a strand of cells to adapt quicker to a changing environment, and mutation rates are tuned in accordance with how hostile the environment is.

So, a single-cell organism adapts to the environment through two mechanisms: 
1) The competition between individual cells for nutrients in their environment, and 
2) The adaptation of mutation rate according to stresses from the environment.

Let’s get together

That’s how cells work. Not only back then, but also now. The cells of today are not that different from a few billion years ago. However, somewhere down the line (about a billion years ago, or so), some cells started to lump up 3. The cells in the goo were already engaged in a crude form of cell-to-cell interaction by exchanging chemical substances. These interactions were made stronger by lumping together, as a way to reach energy supplies that was not as easily available for the single-cell organisms. The multiple-cell organism was born. Here’s a problem with that: Cells compete for nutrients in the environment. This is true whether the environment is a puddle of goo, or if it is bodily tissue in an organism where the goo has been replaced by capillary blood vessels. In order to form multiple-cell organisms, something needs to both turn off the cells’ goo-mentality of competition for nutrients in the environment, as well as the willingness to adapt to tougher conditions through a higher mutation rate, since it is important for the cells in the lump to be very similar and coordinated.

In a human body the lumping together seems to have gotten out of control a bit. We are made up of about 10 trillion cells. That’s ten million million cells. That’s ten thousand billion cells. That’s a lot of cells. What you call ‘you’ is 10 trillion individuals that somehow interact as if they are one. In all of these cells, the urge to be an individual has been turned off. It’s a brave new world. The question is: How?

There seems to be a constant battle between individualistic goo-urges of each-cell-on-its-own, and being complacent within the collective anonymous struggle for the greater good of the organism. It is when the goo-urges take over in a group of cells that a cancer can form. So, why don’t we get cancer all the time??

The battle begins

When cellular collaboration turns into the survival of the fittest and meanest, it leads to the eventual death of all cells. In the body. Of course, the ensuing rotting and decomposing is a feast for other cells…

Imagine a group of cells sitting next to each other in a part of the body. Imagine one of these cells: Elle the cell. There are yummy nutrients abundant, but each of the cells are only allowed to eat a little bit of it. It is believed that there is a complex exchange of substances between the cells, that the cells constantly talk to each other, keeping each other in check, making sure that no-one eats more than what is allowed. It is a self-policing system. And a very communicative and chatty one at that. And that’s fine, Elle is complacent, since she gets enough nutrients to survive and reproduce through splitting once in a while. All is fine. But then something happens. Something in the environment of the group of cells becomes annoying, something is disrupting the communication between the cells. It is not entirely clear what could cause this, probably a combination of things. It could be substances coming from the outside, it could be a wound in the tissue to which our cells belong, it could also be a mutation in one cell in the group making it disrupt communications. Whatever it is, it causes a breakdown in communication between the cells. With the other cells not able to notice, Elle sees no reason to be complacent any more. Why not try and eat all that vitamin-goo her ancestors have craved for billions of years? Let’s go for the goo! Elle eats as much as she can, splits into other cells who are also independent and eat as much as they can. But Elle was not alone, she also stopped watching the other cells, so they also have started eating and reproducing as much as possible. A tumour is born. 

Notice that no-one has had to mutate yet. Also note that the tumour does not come from one cell going bad, but a group of cells. The cells have merely stopped communicating and started acting as separate single-cell organisms. If the competition between cells in a tumour is a peaceful one, the tumour will end up being heterogeneous, consist of many different cells, all with individual strategies to extract nutrients from the environment.4

The competition may also be aggressive. One cell may start mutating, developing poison of which it is itself immune. This poison would kill all cells which are not immune to it, hence leading to a more homogeneous tumour. When the cells start mutating a lot, some cells may get tired of the competition of all these cells in the tumour–why stay there when there are so many non-competitive cells elsewhere? They leave the mother tumour and send metastasis all over the body. In the so-called seed and soil theory from 1889(!), these stray cancer-cells will find a new home in tissue that is similar to the tissue of origin, and with less competition for nutrients.5

This is one reason cancer has not yet been cured: Each cancer tumour contains many struggling and competing cell-strands. If a medicine targets only one of these it may end up helping other strands. Contradictorily enough, it may therefore be easier to cure more aggressive cancers, where the tumours are homogenous, and the medicine can be made to target only that one strand.

Wings anyone? Some experimental evidence

Francisco Duran-Reynals discovered already in the 1930s and ‘40s that the RSV virus is extremely cancerogenic to chicken. He would inject the chicken with the virus in the wing and they would soon develop large and malignant tumours. When he did it on chick foetuses, this did not happen, the foetuses grew up normally and cancer free. These findings were dismissed as poor lab work, it was reasoned that something probably went wrong with the eggs. It was not until 1984 that David Dolberg and Mina Bissell repeated the experiment. When they injected RSV into the wings of chick embryos, the chicks were growing up just fine, despite the fact that they had an extremely cancerogenic substance in their bodies. However, if the wing of the chicken was removed from its body, it would over night develop cancer. 6

In 1975, Beatrice Mintz and Carl Illmensee inserted mutated cancerous tumour cells from a mouse into mouse foetuses. When the mice grew up, they showed no sign of cancer. The mutated cells were behaving as normal mouse cells within the body. These findings have been reproduced many times since.

What the chicken experiments, and others like them, show is this: it is not enough to merely be subjected to a cancerogenic substance for developing cancer. Something else is also needed, something else that reduces the cells’ will to cooperate. Wounding seems to be one such thing, amongst many. When this something else is present, there is a shift in the organ where it happens. All of a sudden the cells in a region stop cooperating, and they start to fiercely fight each other for the nutrients in the environment, such that one or two or three tumours start to grow, all containing a bunch of cells all fighting each other for the food. 

What the mice experiment shows is that tumours and mutated cells have much less to do with each other than often believed. Mutated cancer cells can act quite normally in the right environment, and tumours do not necessarily have to be mutated. But mutated cells inside of tumours can be deadly, as becomes clearer when we enter the realm of the occult.

Something occult happening

One should not be too judgemental of tumours, not all of them are dangerous. It is likely that you have a few right now. Arnold Rich discovered something quite surprising when performing autopsies already in 1935, which has since then been reproduced to great accuracy. These autopsies have revealed that 9% of men in their 20s have at least one tumour in their prostate. In their 30s the number is 27%, and in their 40s its 34%. And that’s just in the prostate. 39% of women in their 40s have tumours in their breasts. Tumorous findings in the thyroid gland are so frequent that they are considered normal. The occurrence of tumours in lung tissue has raised concerns of over-diagnosis of lung cancer detected by screenings. These tumours that go unnoticed are referred to as ‘occult tumours’. So there seems to be another mechanism at work as well which keeps a tumour from becoming a cancer. What keeps a tumour from becoming a cancer? No one knows for certain. We do know some things though, which may hint at the truth.

For example: It turns out that heterogeneous tumours are often less dangerous than homogeneous ones. This could be because the cells in the homogeneous tumours are more aggressive and therefore kill those cells that are not as aggressive, since the dominance of the one aggressive cell-strand is what made the tumour homogeneous in the first place. This could mean that the mutation rate in dangerous tumours is higher than in heterogeneous ones. Remember: To form a tumour, mutations are not really necessary, only a communication break-down between the cells. This could be caused by mutations, but it does not have to be. However, sometimes the homogeneity of the tumour makes it easier to treat, since one medicine at one dosage has the same effect on the entire cancer. This is why chemotherapy is so efficient for treating testicular cancer and some forms of leukaemia.

Another example: Some tumours are not dangerous–until you try to treat them. There have been examples of cancer treatments that are aimed to stop the blood-flow into tumours and thus effectively kill them. The result has been the opposite, the tumour grew more aggressive. The same seems to be the case for some chemo-therapy treatments, which makes some cancers worse. Remember: in a tumour the individualistic goo mentality of each-cell-on-its-own is dominant. If you try to make the environment more hostile for the tumour it may only cause the cells to mutate quicker in order to adapt to the new environment, making the tumour more aggressive in the process. It has been found that the success of some treatments is very sensitive to the exact correct dosage of the chemotherapy. Both too much and too little medicine makes the cancer worse. You’d better rub your tumours the right way.

To summarise

What do cancerogenic substances have in common? It seems as if all of them need to expose cells in our body to heightened stress over a long time, making it harder for the cells to eat and reproduce. Be it DDT, a persistent bacterial inflammation, cigarette smoke, pollution, viruses, or even a repeated exposure to hot beverages. Things that irritate and stress the cells into increasing their mutation rate, just like their forecells have done for billions of years. But that only gives you mutations, and we have seen that mutations do not cause cancer. Unless it happens in a tumour. It may be easier for the heightened mutation rate to occur in a tumour, where the goo-mentality of the cells is already established. But it takes both mechanisms for a cancer to develop, the break-down of cell-to-cell communication, and the increased mutation rate caused by a stressful environment for the cells. Mutations may occur both before and after a tumour is formed. And experiments support this hypothesis, e.g. when mutated cells from cancers are put into a non-cancerous environment they become functional non-cancerous cells, also most people have multiple non-cancerous ‘occult’ tumours, which is considered normal. This all points to that mutations are not harmful, and tumours are not harmful, but mutations in tumours can be deadly.

To summarise: In order for cells to work together for the greater good of the body they need to communicate and hinder each other from being the egoistic bastards their forecells of the goo were. When the communication breaks down between the cells, there is opportunity for tumours to form. When the cells in the tumours start to mutate at a faster rate, the tumours may turn into cancer. Sometimes it can be successfully treated by the refined methods of operations, chemotherapy, or radiation therapy available to us today. Sometimes, even if treated, it I may kill you within months.

Disclaimer: It is tempting to use cell-communication and its breakdown described in this post as an analogy for human society. Unlike humans, however, single cells don’t have a purpose and will which inform their actions. Also unlike humans, cells tend to not have names.

References:

Much of the material in this text comes from this Nature Medicine Review Article:
Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression.
Bissell MJ, Hines WC.
Nat Med. 2011 Mar;17(3):320-9. Review.
There the importance of the chemical environment in causing or not causing tumours are described. Also, it reviews the experiments on chicken and mouse described above and discusses occult tumours.

Information on mutation frequencies and rates of one-celled organisms:
The evolution of mutation rates: separating causes from consequences.
Sniegowski PD, Gerrish PJ, Johnson T, Shaver A.
Bioessays. 2000 Dec;22(12):1057-66. Review.

For a good discussion on why food supplements, including antioxidants, may not be such a great thing after all, read Ben Goldacre’s book “Bad Science” or follow his blog with the same name: http://www.badscience.net/

On how chemotherapy may make some cancers worse:
Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B.
Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS.
Nat Med. 2012 Aug 5. doi: 10.1038/nm.2890.  

 Thinking of Things, 2015.