by Jenny White
Jenny White: Tell me what we should know about cancer?
Michael Freeman: Cancer is an uncontrolled proliferation of cells, so a tumor is actually is a swelling or a cyst, something that isn’t necessarily life-threatening, but a malignancy is something that has the potential to grow and spread in the body and its the spreading in the body as well as the growth that is lethal. We’re still trying to understand fundamental processes that are part of cancer. A recently recognized process involved in cancer, for instance, is autophagy, which means “self-eating.” This is a normal way that cells use to conserve energy and nutrients, and it’s a process that can be used by cancer cells to progress to malignant states. Tumor cells generally are in a very stressful environment, so there’s a Darwinian pressure to select for variants that can overcome various stresses. So if you’re a tumor cell and your descendants have the ability to take in nutrients from this process of autophagy, then you have a selective advantage over other cells that might be killed in the stressful environment.
JW: So basically the Pac-Man cells survive because they eat the cells surrounding them.
MF: They actually eat themselves.
JW: Are there any other cool concepts that are out there? Autophagy, self-eating Pac-Man cells. What else is going on?
MF: There’s another concept that was very new when I was a postdoctoral fellow, but is now very much understood to be a fundamental process in tumor biology, which is apoptosis or programmed cell death. This is a program that cells initiate that causes them to die. It’s basically cell-suicide. There are signaling molecules that can initiate the suicide program that’s built into the cell. This is a normal process that takes place during development. The fingers on your hand were created in part through an apoptopic mechanism, where the webbing between the digits was formed by cells killing themselves. In development, in the formation of the body plan, there’s growth as well as loss of structure. It even happens during normal life as an adult. It’s like what a sculptor does, right? A sculptor creates form by removing things.
JW: How does that fit with cancer?
MF: There are tumor cells appearing in your body every day. Your immune system will recognize these cells as aberrations and they’ll be killed. It’s a complicated biochemical process, but basically the cells initiate a suicide program, though sometimes cells arise that are resistant to those apoptopic signals. And this turns out to be a very important reason that you have malignant progression — you have cells that resist the signals that tell them to die.
JW: And why is that? They just don’t like to be told what to do?
MF: They resist these signals because they have various biochemical pathways inside them that are either activated or disabled. Oncogenes are genes that can cause tumors. But mechanistically what that oncogene might be doing is to elicit, activate or allow certain biochemical pathways that results in a cell that can resist apoptopic signals. You can have a biochemical pathway where A protein signals to B protein signals to C protein, and the ability of A to signal to B is shut down. You have an inhibitor that’s inhibiting the A to B signal. Sometimes to initiate an apoptotic signal, you need a cell-surface receptor that needs to be positioned in a certain way on the cell surface, and it can either not be there or it can be internalized. Genes can be shut down, genes can be activated. There are a lot of different ways to cause this.
JW: It’s amazing that we move around as fully functioning human beings at all if all of these minute things can go wrong all the time.
MF: After being a biologist for many years, I still find it incredible that any organism lives decades when all of the intricate biochemistry that happens has to continue to happen almost flawlessly. You get ill and your body can repair itself. It’s amazing.
JW: What about other cool things? We’ve got Pac-Man autophagy, we’ve got cell-suicide death wishes. What else is going on?
MF: The tumor genome is massively disrupted. Over the course of a tumor’s life, you have chromosome loss, you have gene duplication, you have gene loss, you have DNA rearrangements. The popular culture analogy I like is the Borg, from Star Trek. “You will be assimilated. Resistance is futile.” That’s not a perfect analogy but it shows how things can be reorganized to become virulent.
JW: Except that the Borg use creatures that then become part of them. They don’t kill the creatures.
MF: They don’t kill a creature initially, but you can think of a cancer – including the cells that are disseminated and the secondary tumors that are formed in parts of the body — as an organism. So the cancer is an independent organism inside one’s body that, of course, is dependent on the host living; it doesn’t have a way to replicate beyond the host. It kills the host and then it dies. But in many ways it’s like an independent organism.
JW: But what is the point of this organism inhabiting you if it doesn’t help it to replicate itself. Cancer doesn’t spread, right? Isn’t it a basic biological premise that creatures evolve in order to seed their own kind?
MF: But it does inside an organism. It’s like a virus in the sense that it’ll replicate inside the organism. Viruses can obviously move between hosts, and cancer cells cannot. But within the universe of the host, it’s very much a Darwinian process. You have selection, you have progeny, you have replication, you have death, you have new variants arising all the time. The new variants are being selected. The difference is that the entire universe of the cancer is the patient, and when the patient dies, the universe ends.
JW: So why would you say it’s one organism? Aren’t you saying it’s an organism with offspring that it sends out to different parts of the body?
MF: Human beings have all these symbiotic bacteria living in their gut and elsewhere on their body, so if you look at yourself as an organism, there’s about ten times more bacterial cells that are part of your body than your actual human cells. So what does that mean? Does that mean you should be defined primarily as a bacterial colony?
JW: That’s gross! Boy, that certainly changes my vision of the human body. It’s almost like we’re a small universe in which other small organisms grow, just like we grow on the earth, destroying it as we go along, using up its carbon and its air and wood.
MF: The bacteria will be fine. No matter what we do to the earth, the bacteria will be fine. They’ve been around much longer than us; they’ve diversified tremendously.
JW: How old is cancer?
MF: I don’t know for sure, but I would say that cancer is ancient and it occurred early in association with multicellularity. Jellyfish are multicellular. They’re about 600 million years old; it’s a very ancient lineage. And it would be an interesting question – I don’t know the answer — if they have cancer. If they had cancer then that would be evidence that cancer is at least 600 million years old.
JW: What’s the difference between bacteria and a cancer cell?
MF: The cancer cells that arise in your body are genomically very similar to you, so they’re human. The cell is deranged in some ways, but it can be unambiguously identified as human. A bacterium is a much simpler organism; it doesn’t have a nucleus; it doesn’t have chromosomes arranged the way ours are. So it’s a very different type of creature.
JW: But why do you call cancer a creature? It could be like a skin growth or a mole or something that just has grown out of control.
MF: When you look at cancer cells under a microscope, they’re a colony of creatures. They’re clearly independent from their source. If you’re going to call a single-cell organism like a protozoan a creature, then I think it’s perfectly reasonable to call a colony of cancer cells or even a single cancer cell a creature. I mean, it can crawl around, it can eat, it can respond to its environment. It’s respiring, it’s consuming food; it’s replicating. It’s very much alive.
JW: OK, now all of this is giving me the creeps. It’s much more comforting to think of cancer as something that’s not human, that’s just an invader that you might be able to kick out. So the treatments people are using to try to kill the cells individually are really not dealing with the problem.
MF: You can use the Borg analogy. The Borg takes on new abilities over time because it assimilates civilizations. But when you shoot at the Borg, you know, using some advanced photonic device, you kill the Borg. And then the second Borg comes at you and you kill that Borg. And the third Borg comes at you and you kill that one. But by the time the fourth Borg comes at you, the organism has already adapted.
JW: So you’re telling me that not only are there these creatures in their own universe inside the body, but they’re actually able to learn, take on new abilities.
MF: It’s very much like any other Darwinian evolution in that you produce variants and some of the variants are going to resist your attempts to kill them. I saw some data in 2010 from a colleague who had done whole genome scans of between ten and fifteen metastatic tumors taken from one person. You can think of these tumors as all part of an organism, using this analogy we’re talking about. But in reality when you looked at the genome of these tumors, they were radically different. Much more different than you or me, for example. So tumor cells have the ability to alter their genome in all sorts of ways that normally doesn’t occur. The genome is normally very stable. There are some significant changes that happen with sexual reproduction, but for the most part your genome that’s being replicated throughout your entire life is pretty stable. My genome isn’t that different from yours. But the genomes of these individual tumor cells – at least in this particular case – were radically different.
JW: So the tumor cells were different from the cancer patient, but also different from each other. They’re individuals!
MF: Right.
JW: Is there any good news?
MF: Well, we know a lot about tumor biology now. I started graduate school in the early 1980s and there’s no comparison between now and then. We have a vast reservoir of knowledge now. We have a much greater ability to identify promising drugs than we did ten years ago. The goal I think of most cancer researchers is to get to the point where cancer becomes a chronic disease and it’s managed with medical therapy. I think that’s what people are shooting for.
JW: So when will all this new knowledge turn into new treatments?
MF: That part of it is very disappointing. The rate-limiting step is the means by which drugs that look promising in the laboratory can be tested in humans. This is very expensive. To move one drug through phase 1, 2 and 3 clinical trials can cost upwards of a billion dollars. The only way that can be paid for is through companies, and companies can decide to proceed with that investment or not. There are many situations where you have promising drugs and they’re not ever moved into clinical situations and tested in real patients because the cost is too high. Pharmaceutical companies have to make strategic decisions based on the bottom line, and a lot of that is divorced from science.
JW: What’s the most exciting thing to come out of your lab in the last year?
MF: Two things. One is that we discovered a gene that controls a process where a cell acquires an ability to move rapidly through tissue spaces by deforming its membrane. This is referred to as amoeboid features. We discovered a gene that regulates that process, one of the first ever found. We think the amoeboid properties are highly relevant to the way in which cells can metastasize. This is potentially a signaling network that controls metastasis.
JW: So the amoeboid form allows cancer cells to basically hail a cab and get around the body more quickly than the usual way of cancer cells creeping through tissue, and you’re taking away the car keys. That’s great. What’s the other thing?
MF: We discovered a new type of tumor-derived particle that these amoeboid cells can spit out. These particles, which are not cells, have biological activity, so they can communicate with other cells. They can circulate through the blood and potentially modify and signal cells very distantly from the primary tumor that produced the particle. And they’re large. The significance of the largeness is that you can find them more easily in circulation, and we’ve also shown that you can actually see them in tissue specimens. Their presence predicts aggressive disease. This is a new type of particle that hasn’t been described until now. Since it seems to promote tumor spread, it might serve as an indicator of aggressiveness clinically, which might improve the ability to target the tumor with specific drugs.
JW: So this particle has the ability to kick-start other cells into turning cancerous.
MW: Exactly. Another thing my lab has worked on for a number of years is the relationship between cholesterol and aggressive cancer. Our findings indicate that high cholesterol is actually tumor-promoting in the case of prostate cancer. The implication is that if you take cholesterol-lowering drugs, you might be able to inhibit cancer in some people.
JW: Do you have some words for people reading this who might now be rather depressed?
MF: I think twenty years from now, as long as we don’t pull the plug on our magnificent research efforts here in the United States, what we know now will probably seem very primitive. So it’s best to be humble.