Nae Trainers!

nae-trainersSo, in my last post, I described how different cell populations within an individual tumour can respond differently to specific treatments, and how this could be combated with combination therapy.  In this post, I’m going to describe how tumours respond to these attacks, and why this can be very, very bad news for the patient.

One of the big things that people tend to forget is that cancer cells are derived from a patient’s own body.  Essentially, it is part of them.  And like any other cell in your body, it has built-in survival mechanisms that it uses to keep itself alive.  In one sense, that is what causes cancer – in normal cells, the survival mechanisms are tightly controlled, but in cancer cells the survival mechanisms are out of control (see No Bootees).

Now, if you think of survival from the perspective of the body as a whole, then some of these survival mechanisms are pretty well known about.  Eating.  Drinking.  Breathing.  Sleep.  And even when you zoom in to look just at an individual cell, there are equivalent mechanisms in place.  Now, obviously cells are much, much simpler than whole bodies (naturally!), so the equivalent cell-based mechanisms are simpler, but they work on the same basic principles.   So, cells need nutrients in order to survive, therefore the food you eat gets broken down and then distributed to every cell.  Same with water.   That’s how cells “eat” and “drink”.  Oxygen is extracted from the air you breathe and is transported around your body by your red blood cells where it is passed to every cell.  The cells use the oxygen & nutrients to make energy.  This releases carbon dioxide, which is returned by the blood cells to the lungs, where you breathe it out.   That’s how cells “breathe”.  Cells even have their own growth and rest rhythms.

Likewise, if we zoom out again to look at the whole-body situation, what happens if our body comes under attack from, say, a virus or bacterial infection?  Again, survival mechanisms kick in – namely our immune system.  The immune system is primed to recognise things that shouldn’t be in your body – things that could be harmful – and get rid of them.  And, once again, if we zoom in to the level of an individual cell, the individual cell also has defence systems that recognise things that shouldn’t be there – things that could be harmful – and get rid of them.

Again, I’m not saying that these cellular defences are the same as immune responses.  Your immune response is a very (very!) complicated system of different cell types and agents working together in a myriad of different ways.  And as cells are much simpler than whole bodies, the types of defences you’ll find inside a cell are also much simpler.

You can think of the cellular defences as working a bit like Bouncers in a Nightclub.  Their job is to patrol the cell looking for trouble.  If they see anything that looks dodgy, they grab it and throw it out.  This type of activity is important in normal cells, as it helps to protect against the actions of toxins that may have been ingested accidentally in food.  But the problem is, these survival mechanisms are only trying to protect the individual cell, not the body as a whole.  So, in cancer cells, the defence mechanisms will act to try and keep the cancer cells alive, even if this would be bad for a patient’s overall survival.  And this is what gives rise to therapy resistance.

Ask yourself:  What are cancer treatments for?  Answer: to kill cancer cells.  Next question:  How do they do this?  Answer:  they act like toxins, or poisons which kill the cancer cells.  Now, since cells, both normal and cancer, have defence mechanisms to protect against toxins, how do you think the cancer cells will react to chemotherapy drugs which act like toxins?  That’s right.  They activate their defences.

They send out the Bouncers.

And this is another way that cancer cells resist chemo drugs.  So, while the last post I explained that some cancer cells can resist drugs because they lack the thing the drug targets, you can see that another way they do it is by attacking the drug itself.

The Bouncers grab the chemotherapy drug and “disarm” it by altering its chemical structure so it can’t work anymore (the biological equivalent of twisting its arm up its back).  Then, they frog-march the drug to the edge of the cell and throw it out.

So, even if the cancer cell contains the drug’s target and is susceptible to its action, it doesn’t matter because the drug doesn’t get anywhere near the target.  It gets disarmed & booted out before it can work.

And it gets worse.  Because there is a nasty little twist to the tale.  The way that the Bouncers recognise the chemo drug is by its chemical structure. Chemo drugs, like a lot of toxins, tend to be big, bulky, complicated molecules.  So, when they get switched on, the Bouncers will grab any big, bulky, complicated molecule and get rid of it.

Again, to go back to the Nightclub analogy, think of it like a dress code.  A Nightclub Bouncer spots that some of the clientele are wearing trainers and chucks them out.  It doesn’t matter if they are causing trouble or not.  It doesn’t matter if they are splashing the cash.  The Nightclub has a “No Trainers” rule, so the trainer-wearers get the boot.

“Nae trainers mate,” the Bouncers say, “Beat it!”

And this is also what happens in cancer cells.  A doctor gives a cancer patient a drug.  The patient’s cancer cells activate the Bouncers.  The Bouncers recognise the drug’s big, bulky, complicated structure – its trainers!  So the Bouncers chuck it out.  Therefore the drug doesn’t work.

So, the doctor prescribes another drug.  But!  That drug also has a big, bulky, complicated structure – it also has trainers!  So the cancer cell Bouncers get rid of that one too.  Same with the third drug prescribed.  And the fourth.  And the fifth. And so on…..

…And that is what can be so nasty about this process.  Any cancer cell which activates its defences to become resistant to ONE drug, is ALSO IMMEDIATELY RESISTANT TO LOTS OF OTHER DRUGS AS WELL!

This process is called Multidrug Resistance and while it is not found in every cancer type (thankfully!), it is a hallmark of aggressive cancers.  In fact, you could say that it is why these diseases are aggressive in the first place – they grow and spread so much because standard chemo simply doesn’t work on them.  Their Bouncers are too good.

Now, as you would expect, this is something that attracts a lot of research.  Some groups are trying to develop new drugs which don’t get targeted (ie. without trainers).  Others are investigating the defence systems to try and find ways of deactivating them – of getting rid of the Bouncers. If either approach can be made to work, it would be a big step forward in the treatment of aggressive disease.  Until then…..the Bouncers will keep on working.  And the cancers will keep on growing.

Review article (2000). Cancer multidrug resistance Nature Biotechnology, 18 (Supp) DOI: 10.1038/80051
AG McCluskey (2016). Nae Trainers! Zongo’s Cancer Diaries