American Association for Cancer Research

Basic Biology and Cancer

The Six Hallmarks of Cancer

There are six hallmarks to most, if not all, cancers that are essential for carcinogenesis, or cancer formation. If you have a cancer, then the behavior of that cancer is incorporating all six of these characteristics. If it is missing one of these characteristics, then it’s very likely that you don't have cancer. These six hallmarks are: growth signal autonomy, which means the cell grows even when it’s not getting a message to grow; not paying attention to the stop signs, which means the cell ignores messages telling it to stop growing; evasion of apoptosis, which means a cell avoids all the messages that tell it to die; angiogenesis, which means the ability to grow new blood vessels; unlimited replicative potential, which means that a cell keeps replicating no matter how many times it has already done so; and invasion and metastasis, which means the cells are moving into areas where they should not be.

I’ll now explain these hallmarks in more detail. When cells are normal, they only grow when they should. Let’s go back to the example I used before, where I’ve injured my skin. Remember the epidermal growth factor I mentioned, which plays a role in how cells grow and divide? Well, when I injure my skin, the epidermal growth factor goes to the skin cells and says, “Skin cells start multiplying.” For the skin cells to do this, the growth factor has to bind to the epidermal growth factor receptor in the cell. This sends a lightning bolt to the nucleus that says, “Divide!” And then the cell divides.

If there is more growth factor around, then the cells will continue to divide. But if there is no growth factor present, they won’t; they need that external signal from the growth factor to act. Cancer cells are cells that are no longer dependent on this growth factor. This means that even when there is no growth factor present they are able to keep sending that lightening bolt to the nucleus of the cell that tells it to divide. They are able to do that because genetic mutations have occurred inside the cell that produce a protein which tricks the cell into thinking that the receptor is getting growth factor when in fact it isn’t. In other words, the genetic mutation turns the switch to grow to the “on” position, and then keeps it on. It has short-circuited the growth factor pathways, and that leads to unregulated growth.

I mentioned earlier that for a cell to be a cancer cell it has to have unregulated growth. That’s one of the hallmarks of cancer. But just having this unregulated growth isn’t enough. Other signals must be affected as well. One of these is the signal that tells a cell to stop growing. Let’s go back to the skin example. When my skin is injured and the skin breaks down, growth factor comes in to tell the cell to grow. But there are also other signals that come in that tell the cell to stop. In a normal skin cell, the cell would send out a message, called a growth inhibitory signal, telling the other cells it has made contact with nearby skins cells and that no more cells are needed. But if that skin cell were a cancer cell, it would have acquired mutations that keep it from paying attention to these growth inhibitory signals. So even though the skin has all the cells it needs, a cancer cell would keep growing and replicating. It wouldn’t care that no more cells are needed.

Another hallmark of a cancer cell is that it has the ability to evade death, or apoptosis. It’s as if the cell has a bulletproof vest on; nothing can stop it. Normally, cells receive a death signal. What happens when you smoke and you start coughing? Well, your normal cells are getting hit with an insult and they are dying, which causes you to cough up all sorts of things. It’s the same when you get a sunburn. The skin sloughs. Why? The cells are dying in response to UV damage, and the sloughing is the removal of these cells by this programmed cell death in response to damage. These cells have been told that they have to get out of the picture. But cancer cells evade those signals. They’ve acquired mutations that disrupt the death pathway and that keep the nucleus of the cell from receiving the “It’s time to die” signal. So instead, it just keeps on going.

How do cells know when to stop dividing? If I took one of my blood cells out of my body and I put it in a Petri dish, it would divide; it would divide; it would divide; it would divide—and then it would stop. No matter what I did to it at that point, it wouldn’t keep dividing. It would just stop, which is amazing. How does it know how to stop? Why can't I get that damn thing to grow? Well, every time a normal cell divides into its two daughter cells, something called a telomere on the cell’s chromosome gets shorter.

The telomere is a marker designed to keep track of how old a cell is based on how many times the cell has divided. Over time, as the cell makes more daughter cells, the telomere gets shorter and shorter; and when it gets too short, the cell won’t divide anymore, even if growth factor is present. A cancer cell has the ability to keep its telomeres from getting really short. And because the telomere isn’t getting shorter, the cancer cell doesn’t think it’s getting older; instead, it thinks it needs to keep dividing. You may have heard of telomerase, which is an enzyme found in the telomeres. We’re creating drugs that target telomerase because it plays a role in this process. It may be that inhibiting telomerase will shorten the telomeres, which will, in turn, stop the cancer cells from growing and dividing. That’s something that is currently being studied.

Another hallmark of a cancer cell is that, unlike a normal cell, it is able to form new blood vessels, a process called angiogenesis. You can't go wandering in the desert forever, right? Why not? Well, you need water and you need nutrition. It’s the same with a tumor. If I have a tumor that's on my hand, it can only get so big before it requires more and more nutrients to keep growing. Normal cells depend on a set amount of blood vessels to provide them with the oxygen and nutrients they need. In contrast, cancer cells start sending out messages that say, “Send me more blood vessels.” If we put normal cells into a mouse, no vessels come. But if you put a cancer cell into a mouse, you can literally watch that cancer cell call blood vessels to itself. It will replicate a few times and then die, but it will call blood vessels. This is called angiogenesis, and this is what led to the development of drugs that are anti-angiogenic. Anti-angiogenic drugs target the proteins on the cells or the receptors on the blood vessels to get the cancer to stop recruiting blood vessels.

It now may be becoming clear to you as to why an anti-angiogenic drug or a telomerase inhibitor alone doesn’t cure cancer. The problem is that each of these drugs hits just one of the things that keeps a cancer cell going. But there are other things that need to be stopped, too. That’s why we need many drugs, and that's why basic science is so important. You have to understand the process of normal cell growth to understand abnormal cell growth. You have to understand normal angiogenesis to understand what is excessive and to know what to target. This is why promoting basic science research is so very important.

Finally, the last hallmark: invasion and metastasis. A normal cell or a benign tumor sits in its box. It doesn't metastasize. It doesn't spread. It maintains its location in the body. Generally, normal cells don't migrate. You won't find a liver cell in the brain. You won’t find a colon cell in the liver. It doesn't happen. But cancer cells, through mutations, through the change of the alphabet, make proteins that tell the cells to grow, to ignore stop signs, to evade death, to recruit blood vessels, and, once they’ve done that, to leave where they are and to go to other parts of the body. A tumor’s ability to do this is really incredible. For invasion and metastasis to occur, the DNA inside a cancer cell has to tell the cell to move into and through the blood vessels. Then, when the cell gets to another organ, the DNA has to tell it to get out of the blood vessel and to make a home there by attracting new blood vessels. It’s amazing. It’s like one of those Arnold Schwarzenegger movies—The Terminator. This is invasion and metastasis, and it is what distinguishes a malignant tumor from a benign tumor.