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Why Do Cells Turn Cancerous? · So That's Why

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Jen: Welcome to the So That's Why podcast, where we unpack the
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science behind everyday questions.
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I'm Jen.
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Chris: I'm Chris.
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Matt: And I'm Matt.
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Jen: So before we start, a quick heads-up about today.
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Today is about the biology, what physically changes inside
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a cell to turn it cancerous.
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So we're not gonna be looking at causes, risk, or anyone's diagnosis.
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So if this is a heavy subject for you right now, it's completely
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okay to sit this one out.
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Chris: Yeah, and I think it feels important to say that plainly, doesn't it?
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Mm. Because cancer really is a heavy topic.
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Mm-hmm.
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But it's something we get asked about all the time, so today we're aiming
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to get stuck into the science, really because the related cell biology
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itself is one of the most extraordinary stories the body has to tell.
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Matt: Which is good, because I'll be honest, this is one of those topics I've
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steered away from, uh, a little bit, and a lot of people, I think, do the same.
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It feels like a massive topic, doesn't it?
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Jen: Yeah, and I think that's really honest, and it's part
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of why we wanted to do it.
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So here's the question.
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Your body will make tens of billions of new cells today alone, and to
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make each one, it copies three billion letters of DNA, and almost
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every copy comes out flawless.
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So the real puzzle isn't why cells sometimes go wrong,
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it's why they so rarely do.
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But why do cells turn cancerous?
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Chris: Yeah, and I think before getting into it, that scale you
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mentioned there, Jen, is like, it's so important to keep in mind.
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So over a lifetime, that's tens of trillions of cell divisions, each one
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copying what's effectively a three billion letter instruction manual.
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Matt: Which is crazy.
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Jen: Yeah.
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Can't get your head around it
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Matt: at all.
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Right.
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I mean, that would take a supercomputer, uh-
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Jen: Yeah
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… Matt: so, uh, uh, 'cause my body, like, is doing this sort of copy job, isn't it?
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This sort of big copying, and it's mostly getting it right- Mm … which
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is, I mean, I can't copy a phone number without messing up a few of the digits,
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so how my body does this, I have no idea.
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Jen: I know.
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Honestly, I'm the same.
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But you know, that's the, it's the right instinct.
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So errors do happen.
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Um, but the remarkable part is actually how much proofreading and
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repair sits on top of it all to catch them before they even matter.
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Chris: Which, let's be honest, this is really what it all comes down to.
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So cancer isn't one dramatic event.
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It's what happens on the very rare occasions- Mm-hmm … where a
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series of those safeguards fail in the same cell one after another.
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Jen: Okay, so let's start with what a normal cell does, because you can't see
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what's broken until you know the rules.
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So a healthy cell only divides when it's signaled to.
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It does its specific job, and here's the one people forget or maybe don't know.
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It dies on a schedule too.
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Matt: So so my cells are programmed to die.
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Jen: Mm-hmm.
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Matt: Sounds a little bit like a fault, not a feature.
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Not gonna lie.
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Chris: Actually the opposite of a fault, and it's called apoptosis,
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which is a controlled self-shutdown the body uses to constantly clear
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out cells that are old, that are damaged, or that are no longer needed.
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Matt: So apoptosis.
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Well done.
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Sounds like a pop group, isn't it?
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It
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Jen: does.
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Matt: Apoptosis.
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Is a cell then doing the responsible thing and stepping aside when it's supposed to?
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Jen: Yep, and that's the deal that a cancer cell breaks, so it stops obeying
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any of those rules, not because anything invades from the outside, but because
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its own DNA instructions get rewritten.
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Chris: That's it.
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And, uh, to see how that rewriting happens, I think it helps to know
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what the instructions are made of and how they get copied, doesn't it?
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Matt: Yeah.
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Well, go on then, because DNA is one of those words I use confidently- … uh,
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but cannot really ever explain, and don't ask me what it stands for.
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I just would not know.
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Jen: So most people are the same.
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Okay.
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So DNA, deoxyribonucleic acid.
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Matt: You're just showing off now,
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Jen: aren't you?
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Yeah, I am.
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Chris: We can ask you to, uh, pronounce that at the end.
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Yeah, yeah,
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Matt: yeah.
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Jen: It's a long instruction written in a four-letter alphabet.
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So you've got A, T, C, and G, and they're also called bases,
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and they pair up in a fixed way.
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So A always bonds with T, and C always bonds with G.
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Matt: So it's two matching halves, and each half tells you
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what the other one should say?
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Jen: Mm-hmm.
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Chris: Yep, and that's what makes the copying possible.
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So you might have seen the classic DNA double helix structure.
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Matt: Mm-hmm.
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Chris: And when a cell divides, that double helix basically unzips, uh,
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down the middle, and each strand is used as a template to rebuild
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its partner one letter at a time.
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Matt: So the pairing rule is a built-in check then.
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If one side reads A, the new partner has got to be a T or something's gone wrong.
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Jen: Yeah, and that check, it's why, it's why most of the errors get caught.
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But across three billion letters, some slip through, and they
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come in three different kinds.
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So you can have them where a letter can b- can be substituted for the
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wrong one, or an extra letter can be inserted, or one can be deleted.
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Matt: Okay, and I'm guessing, and, you know, the magic scientist that I am,
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that an insertion or a deletion does more damage maybe than a straight swap.
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Chris: Well, you get a science point there, Matt, 'cause yes, usually.
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And it's because, um, DNA code is read in three letter blocks, and
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each block codes for one amino acid.
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And an amino acid, as you may know, is a building block of a protein.
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So if you substitute one letter, you can often change just a single block.
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But if you insert or delete one Every block after that shifts along by
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one, and it's called a frame shift.
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And basically from that point, the rest of the instruction reads as nonsense.
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Matt: A frame shift.
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Mm. Love that phrase.
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So a substitution is a typo in one word, but an insertion or
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deletion knocks the whole sentence out of step from that point on.
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Jen: Right.
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And any of those, like a substitution, an insertion, or a deletion, is
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what we mean by a mutation, and that is a permanent change to the
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DNA sequence in that one cell.
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Matt: Okay, so if these slip through, then often, three billion, uh, why
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aren't we constantly in trouble?
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Jen: Because the vast majority are harmless, so they'll land in stretches
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of DNA that don't actually code for anything, or they get repaired within
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minutes, or the cell triggers apoptosis.
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So a mutation, it only starts to matter when it hits one particular kind of gene.
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Chris: Yeah, and that's such an important thing to remember, isn't it?
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To kind of put it into context.
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Um, so there are two key families that count here, and the first is what
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we, we call, um, proto-oncogenes, and they normally drive healthy growth.
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So they tell cells to divide when there's a real signal.
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However, when you mutate one of those proto-oncogenes, it becomes
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an oncogene, meaning it's locked permanently on, so the cells divide
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nonstop even if there's no signal at all.
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Matt: Mm.
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So the gene whose whole job it is to say, "Grow," gets stuck in the in the
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forward position, in the on position, still shouting, "Grow," when nothing
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is actually asking it to, I'm guessing.
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Jen: Yeah, stuck, shouting, "Grow." Um, so you mentioned one family.
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The second family is a tumor suppressor gene.
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So they do the opposite job.
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They hold growth back, um, repairing DNA and calling for apoptosis
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when a cell is too far gone.
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But in cancer, those get switched off.
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Chris: They do, and the most important tumor suppressor is one you probably
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heard us talking about elsewhere, and it's P53, which is also nicknamed
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the, the Guardian of the Genome.
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Jen: Feel like I wanna salute it when you say Guardian of the Genome.
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Chris: Well, it's important enough, I think it, it, it deserves it.
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Yeah.
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Because when DNA's damaged, uh, P53 either halts the cell so it can be repaired,
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or if it's beyond saving, it orders that apoptosis, well, that cell death.
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And P53 is faulty in more than half of all cancers.
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Matt: Mm.
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So losing then P53 doesn't, uh, just allow damage, it removes the very thing
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that would have caught the damage.
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So it feels like a double blow when 53's not doing its job.
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Mm.
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Chris: It really is, and this is why it takes so long.
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So a cancer cell can carry hundreds of mutations, but most of them are
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passengers, so just effectively along for the ride doing nothing.
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It's that handful of driving mutations that matter, and it usually
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takes, uh, six or more distinct drivers stacking up in one cell
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line to kind of do the main damage.
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Jen: And there's a detail on the tumor suppressors worth having.
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So you inherit two copies of each, so both have to be knocked out
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before that safeguard is truly gone.
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It's called the two-hit rule, and it was first worked out in 1971 by
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a scientist called Alfred Knudsen.
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Matt: Not Alfred?
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Jen: Yeah, Alfred.
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Matt: Okay.
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RL.
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So RL.
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Yeah.
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So that's why I guess some tumor … uh, some cancers may
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be run in families, I'm guessing.
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If you're born already missing one copy- Mm … you only really need the
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second hit rather than the two, and you maybe are a step closer to the edge.
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Chris: Yeah, it's true, but I think it's really important to say it doesn't mean
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anyone's fate is sealed because of that.
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It just means that the count starts from a different place.
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Jen: Yeah.
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And once a few drivers are in, it can start to accelerate because some
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of the genes that get knocked out are the DNA repair genes themselves.
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Matt: Okay.
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I don't … I'm not sure I like where this is going.
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So once the proofreaders are gone, the errors, I'm assuming, then pile up faster.
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Chris: Yeah, and that's the honest, and I think fair to say,
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the unfortunate picture here.
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Mm. Because the whole genome in that situation becomes unstable.
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It's what's called a mutator phenotype, so more drivers arrive sooner,
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and the process that crept along for years can appear to speed up.
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Matt: Which reframes something for me, I guess.
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So when people say cancer appeared suddenly, it probably wasn't sudden.
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It had been building up maybe for a long time, and it just sort of
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crossed the, a line late on perhaps.
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Jen: Yeah, it's true for a lot of cancers.
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What looks sudden is usually the visible end of a long, quiet process.
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Chris: Yeah, that's right.
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And, um, moving around, there's one more layer worth talking about, but I will
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be up front that it's, it's newer, and it's still kind of developing in cancer
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research, and this is the concept that cells can also silence genes without
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changing the DNA letters at all.
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Matt: Hang on, so you can switch a gene off without editing it.
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How does that work?
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Jen: So the main route is a chemical tag called methylation.
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So the cell adds a methyl group to a gene's control region, and it goes quiet.
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So not one letter is changed.
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The instruction's still there, the cell just can't read it.
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And in cancer, that can switch off those same tumor suppressor and repair genes.
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Matt: So you get the same result as a mutation, an off switch, but with nothing
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you could spot in the sequence itself?
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Chris: Broadly, yeah.
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And, um, yeah, it's quite incredible really, isn't it?
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Mm. Not, not necessarily in a positive way.
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Jen: No.
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Chris: Uh, but, you know, I'll stress again, this is, this
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research is still maturing, but it's clearly part of the picture.
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Um, but it's fair to say, you know, it's a layer that we understand less
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completely than the mutation point.
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Jen: Mm-hmm.
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And it's worth also saying cancer isn't one thing, so it's a family of diseases
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in different tissues that share the same story, which is part of why no
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single treatment fits all of them.
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Matt: So even a single tumor, I'm guessing, isn't all identical cells?
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Chris: Correct.
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That's usually not the case.
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Um, as those cells keep dividing, they pick up different mutations
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along the way, so a tumor is usually a mixture of slightly different
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versions, and that mixture is exactly why treatments can be so stubborn.
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Matt: Ah, so the, a therapy then, I guess, clears out most of the cells- And the
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few that happen to be different seem to survive and grow, and that variety, I
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guess, is what makes it so hard to beat.
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Jen: Yeah, it is.
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And by the time a cell has gathered enough drivers, it's picked up a whole set of
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abilities a normal cell would never have.
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Chris: Yeah, and the classic list of, of those things is sometimes
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called the, the hallmarks of cancer.
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So it grows with no signal, it ignores every stop signal, and it
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refuses to undergo apoptosis or cell death, so it keeps accumulating.
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Jen: Mm.
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Matt: So it's broken then.
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Uh, it's broken all three of the rules we started with.
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It grows uninvited, it won't stop, and it won't step aside.
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Jen: All three, and then it adds more.
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It, it becomes effectively immortal.
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So normal chromosomes have protective caps on them called telomeres that shorten with
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each cell division until the cell retires.
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But cancer cells switch repair enzyme telomerase back on to rebuild them.
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Matt: So the cell reactivates an enzyme that resets its own
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counter and cancels its retirement?
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Jen: Mm.
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Matt: Sounds all a bit futuristic, a bit AI, a bit alien invasion-
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Jen: Yeah
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… Matt: if I'm honest.
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Chris: Yeah, and it's a genuinely strange trick.
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And there's one more that I'd say is arguably even more sneaky,
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because your immune system, which is obviously amazing, it's constantly
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patrolling for abnormal cells.
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And so c- a cancer that survives has learned to hide, basically.
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So it stops showing the surface flags that mark it as faulty, and
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it puts out checkpoint signals.
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So we're talking about molecules like, uh, PD-L1, which is a, a protein that
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tells immune cells to stand down.
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Jen: And there was a study in the Nature journal in 2025, and that
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found that it can go further still.
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So the cancer cell physically passes its own faulty mitochondria,
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the parts that generate a cell's energy, into the immune cells sent
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to destroy it, jamming their power supply so that they can't fight back.
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Matt: So it doesn't just hide from the immune system, it disables then
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the very cells sent to kill it.
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Every one of those, uh, is another rule it's learned to break then.
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Chris: That's it, and, and that's probably the natural place to end that mechanism.
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So with all these safeguards, the question is, you know, why does
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the cell not just stop itself?
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Um, and the important point here, when you go back to those millions
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and trillions that we talked about, is it almost always does.
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Matt: Mm. Yeah, and that's the bit to focus on, isn't it?
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Because after all, um, the, all what we've talked about is incredibly
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easy to feel like the odds are stacked against you and terrible.
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Jen: Yeah.
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They really aren't, though, and that's what we'd want people to take away.
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Given the sheer number of cell divisions every day, cancer is genuinely rare.
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So the safeguards catch the overwhelming majority, and it's only the very unlucky
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pile-up of failures in the same cell over a long time that gets through.
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Chris: Yeah, and importantly, every one of the steps we've named is now
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something that research c- can target.
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Mm.
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Jen: And
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Chris: that's from, uh, drugs that block oncogenes to ones that switch
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the immune system response back on.
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And so understanding how the cell breaks each rule is what tells us how to step in.
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And, and let's be honest, the advances are still incredible
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if you think where we are today-
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Matt: Yeah.
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Chris: Yeah … versus even 10 years ago.
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Jen: Absolutely incredible.
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Absolutely, yeah.
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Yeah.
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Matt: Yeah, they really are.
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Okay, so let's bring this home.
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Our original question: Why do cells turn cancerous?
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Jen: Because a single cell accumulates driver mutations
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that break the rules it lives by.
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So the proto-oncogenes that say grow get locked on, the tumor suppressors
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that say stop, repair, or self-destruct get switched off, and the safeguards
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that will catch all of that fail too.
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So you stack up enough, usually over years, and the cell stops
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being cooperative, um, with the body and starts acting for itself.
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Chris: Yeah.
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A- and as we said before, the thing to keep firmly in mind here is that
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it's rare- Mm … precisely because the body is so good at catching it.
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So what we're describing is the exception that slips through an
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extraordinary amount of protection.
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Jen: Mm.
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Matt: And weirdly, I find that reassuring rather than frightening, which is
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perhaps not how I felt at the start of the conversation about cancer.
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Jen: Yeah.
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It's definitely helpful to understand the process in this case.
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So that's why cells turn cancerous.
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That is it for this week.
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Make sure you hit that subscribe button and tell us in the comments what
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questions you'd like us to explore.
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Thanks for geeking out with us.
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But for now, that's it from me.
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Matt: That's it from me.
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Chris: And that's it from
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me.
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Jen: Bye for now