Skip to 0 minutes and 15 seconds Now we have seen that cancer as a multi-step process, and that mutations and tumor suppressors and oncogenes allow these steps to occur, we look in more detail at what aspects of a cell’s behaviour needs to change to allow it to form a malignant tumour. The Hallmarks of Cancer hypothesis was established by Douglas Hanahan and Robert Weinberg. And this week, we’ll have a closer look at the details of what they proposed. For normal, healthy cell to acquire the properties of a cancer cell, there needs to be six alterations to normal cell function, and these are called the hallmarks of cancer. These are, one, self-sufficiency in growth signals. Two, insensitivity to anti-growth signals. Three, evading cell death. Four, unlimited potential to replicate.
Skip to 1 minute and 6 seconds Five, the ability to form new blood supply. And six, the ability to invade and grow away from the original site. These capabilities can be acquired in any order, but only once most or all of these capabilities are obtained does a healthy cell become a cancer cell. The requirement for all six observations to take place for a cancer to develop also explains why cancers are relatively rare over the average human lifetime.
Skip to 1 minute and 39 seconds Now, let’s look at the first capability in more detail, which is self-sufficiency in growth signalling. A normal cell does not grow without getting external growth signals, which can be from growth factors, which diffuse into the local area; signals from the material surrounding the cells, which we call the extracellular matrix; or direct signals from neighbouring cells. However, a cancer cell needs to be independent from these signals, and there are several ways in which it can achieve that. For example, it can produce its own growth factors, which effectively keep it stimulated to grow and divide. Alternatively, a cancer cell can increase the expression of growth factor receptors, meaning that it can be overstimulated by normal levels of growth factors.
Skip to 2 minutes and 30 seconds Growth factor receptors can also become constantly active and send growth signals regardless of whether there are growth factors present or not. The interaction between a cell and the extracellular matrix is achieved via receptors called integrins. There are many types and a cancer cell can change the integrins it expresses to favour ones that stimulate cell growth. Mutations at several points along the growth signalling pathway itself can allow it to become constantly active and render the cancer cells independent of external growth signals. A cancer cell can also make neighbouring cells produce growth signals. These growth signals sometimes have a double function, also acting as survival signals.
Skip to 3 minutes and 20 seconds So certain mutations can actually deal with self-sufficiency in growth signals, as well as evading apoptosis at the same time. The second capability is insensitivity to anti-growth signals. In a normal tissue, anti-proliferative signals prevent cells from excessive growth. These include soluble anti-proliferative signals and signals from the extracellular matrix. Like the growth factors, these signals are received by dedicated receptors. Anti-growth signals can stop cells from proliferating temporarily by putting them into the G0 stage of the cell cycle; or more permanently, by driving them into senescence. Cancer cells find ways to ignore signals from the cell cycle checkpoints so that growth can occur even in the presence of growth inhibitor signals.
Skip to 4 minutes and 17 seconds This can be done, for example, through down regulation of the receptors or the expression of dysfunctional receptors. The third capability is evading apoptosis. Apoptosis, or programmed cell death, occurs as a safeguard mechanism if anything goes wrong in the cell. Damage and mutations normally trigger apoptosis and cancer cells must, therefore, be capable of avoiding it. There are two main aspects to apoptosis. One, the sensors, which sense for cues that cell death is required, and two, the effectors, which accomplish the apoptotic process in response to the activation of the sensors.
Skip to 5 minutes and 2 seconds The sensors respond to a wide variety of signals, including DNA damage; soluble death signals; signalling imbalance; survival factor insufficiency; low oxygen, which we call hypoxia; and signals from the extracellular matrix or neighbouring cells. Cancer cells can evade apoptosis through mutating and inactivating the sensors, thereby reducing the apoptotic signal, or by mutating and inactivating the effectors so that the apoptotic cascade cannot finish. Cancer cells can also upregulate oncogenes, such as BCL2, which are anti-apoptotic and prevent the apoptotic programme. The fourth capability is limitless replicative potential. Once the cell has acquired self-sufficiency in growth signals and sensitivity to anti-growth signals and evasion of apoptosis, it has effectively uncoupled itself from extracellular signals.
Skip to 6 minutes and 7 seconds But is still not fully capable of becoming a tumour cell as each cell has an intrinsic mechanism to limit the total number of replications. This must be overcome in order for a cell to be able to multiply indefinitely. The extremities of each chromosome are capped by repetitive sequences called telomeres, here in red. They protect the DNA, but are shortened at each replicative cycle until they reach a threshold after which the cell can no longer divide. Cancer cells can overcome this by, for example, upregulating an enzyme called telomerase, which lengthens the telomeres at each cycle and therefore maintains telomere length and replicative potential. The fifth capability is angiogenesis, the formation of new blood capillaries.
Skip to 7 minutes and 0 seconds Once cancer cells are able to proliferate, the tumour is restricted in size by its need for oxygen. Cancer cells must be able to induce and sustain angiogenesis in order to provide enough oxygen and nutrients for the growing mass. Normal cells produce some soluble factors, which promote angiogenesis, and others which inhibit it. Cancer cells sustain angiogenesis by producing more of the promoting factors, such as VEGF or less of the inhibitory, and the balance therefore switches to a pro-angiogenesis environment. Enzymes called proteases can also liberate soluble factors stored in the extracellular matrix by degrading it, again, creating a pro-angiogenic environment. The sixth capability is tissue invasion and metastasis.
Skip to 7 minutes and 54 seconds Malignant tumour cells start to invade surrounding normal healthy tissue, and eventually metastasize to distant sites with serious effects for the patient. Cancer cells are bound to the extracellular matrix and neighbouring cells through a variety of surface receptors, such as e-cadherin, most of which also regulate survival and proliferation. Cancer cells can mutate these molecules, produce less of them, or alternatively make proteases, which degrade them. Metastasising cells also express different proteins, which can bind to the specific extracellular matrix found in distant issues. Cancer cells can also direct stromal and immune cells to degrade the extracellular matrix. As you can see, oncogenesis is a multi-step process, which involves a number of changes in the cell.
Skip to 8 minutes and 50 seconds As most of these are required for mutations, agents which increase the rate of mutations therefore increase the likelihood that a normal cell will become a cancer cell. In normal cells, DNA damage and chromosome alterations are detected, and the cell enters apoptosis or growth arrest. Cancer cells overcome this defence, either by mutating sensors of damage or effectors of cell death or growth arrest. It is now clear that tumours do not result simply from the excessive growth of one cell, but also involve neighbouring cells, blood vessels, and the extracellular matrix.
Skip to 9 minutes and 29 seconds In the next video, we’ll have a closer look at some of the fundamentals we’ve outlined here, and move on a step further into discovering why a cell can get out of control.
The hallmarks of cancer
Dr Camille Huser describes six key ‘hallmarks’ of cancer.
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