What Is Cancer? When a Cell Stops Obeying the Rules
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A human body replaces about a hundred billion cells a day, each division copying three billion letters of DNA, and the copying is not perfect. Most errors are harmless, most of the rest are repaired, and most cells that carry a dangerous one are made to destroy themselves. Cancer is what happens when, in one cell, enough of those safeguards fail at once that it begins to divide without permission and its descendants do the same. It is not an infection or a foreign thing; it is the body's own cells, following the rules of evolution inside a body that depends on cells not doing so.
A disease of the genes
Every cell carries genes that tell it when to divide and genes that tell it when to stop, and cancer needs both to go wrong. The accelerators are the oncogenes, normally switched on briefly when a tissue needs to grow and switched off again; a mutation can jam one on. The brakes are the tumour suppressors, of which the best known is p53, a protein that checks the DNA before division and orders repair or suicide if it finds damage; it is disabled in about half of all cancers. A single mutation is not enough. A cell typically needs half a dozen, accumulated over years, which is why cancer is mostly a disease of age and why the rare cancers of childhood often follow a different path, a minority of them involving a gene inherited already broken.
The mutations come from several sources: copying errors in ordinary division, which no one can avoid; chemicals that damage DNA, of which tobacco smoke is the largest single cause of cancer in the world; radiation, including the ultraviolet in sunlight; some viruses, such as the papillomavirus behind cervical cancer, which carry genes that disable the brakes; and chronic inflammation, which keeps cells dividing in tissues that should be resting.
What a cancer cell has learned
In 2000 two biologists, Douglas Hanahan and Robert Weinberg, listed the capabilities a cell must acquire to become a dangerous cancer, and the list has organised the field since:
- •Dividing without an external signal to do so
- •Ignoring the signals that tell it to stop
- •Evading apoptosis, the programmed suicide of damaged cells
- •Dividing indefinitely, by rebuilding the caps on its chromosomes that normally shorten with each division and limit a cell's lifespan
- •Growing its own blood supply, by secreting signals that draw in new vessels
- •Invading neighbouring tissue and travelling to distant sites
- •Rewiring its metabolism and hiding from the immune system, added in the 2011 revision
Why it spreads
A tumour that stays where it started is rarely fatal; surgeons remove it. What kills is metastasis, the spread of cells from the original site through the blood or lymph to lodge and grow in the lungs, liver, bones or brain, and about ninety percent of cancer deaths are from metastatic disease. Spreading is hard for a cell: it must detach, break through the tissue's boundary, survive in the bloodstream, which destroys most of the cells that enter it, escape at a distant site, and grow in a foreign environment. Few of the millions of cells a tumour sheds manage all of it, but a large tumour sheds millions every day. The stages of a cancer, from one to four, measure how far this has gone, and the reason screening for breast, bowel and cervical cancer works is that a tumour found at stage one is a local problem.
How it is fought
Surgery, radiation and chemotherapy were the three tools for most of the twentieth century, and they remain the main ones. Surgery removes what can be seen; radiation damages the DNA of cells in its beam, which kills dividing cells faster than resting ones; chemotherapy poisons cell division throughout the body, which is why it also attacks hair, gut lining and bone marrow, the normal tissues that divide fastest. Since the 1990s two new kinds have been added. Targeted drugs block the specific broken protein driving a particular cancer, the first and most famous being imatinib, which turned one form of leukaemia from a death sentence into a chronic condition in 2001. And immunotherapy releases the brakes on the patient's own immune system, which has usually recognised the cancer and been told by it to stand down; the checkpoint inhibitors that do this, first approved in 2011, have produced lasting remissions in melanoma and lung cancer that nothing before them could.
The numbers
About one person in two in a rich country will be diagnosed with cancer in their lifetime, mostly after sixty, and the rate rises as other causes of death are pushed back. Survival has improved steadily: in Britain half of people diagnosed now live at least ten years, against a quarter in the 1970s, with the gains uneven, very large for testicular cancer, leukaemia in children, breast and prostate cancer, and small for pancreatic, lung and brain tumours. Prevention remains the larger lever. Around four in ten cases are attributable to things that can be changed, tobacco above all, then obesity, alcohol, sunlight and the infections that vaccines against hepatitis B and papillomavirus now prevent. The disease is as old as multicellular life, has been found in dinosaur bones, and is the price of being made of cells that can divide.
Why treatments can stop working
A tumour is not a uniform mass of identical cells. Because cancer cells keep acquiring new mutations as they divide, a tumour becomes a population of related but different cells, and different parts of the same tumour can carry different genetic changes. When a drug is given, it may kill most of the cells, but any that happen to carry a change making them resistant survive and go on dividing. Months or years later the cancer returns, now made mostly of those resistant descendants. It is natural selection happening inside one patient, the same process that produces antibiotic-resistant bacteria.
Knowing this has shaped how cancer is treated. Doctors often combine drugs that attack a cancer in different ways, on the reasoning that a cell is far less likely to be resistant to several at once. When a targeted drug fails, a new biopsy can show which mutation allowed the escape, and in some cancers a second drug has been designed specifically to block that route. Blood tests that detect fragments of tumour DNA, sometimes called liquid biopsies, are increasingly used to watch for resistant cells emerging, so that treatment can be changed before the cancer grows large again.
Why elephants rarely get cancer
If every cell division carries a small chance of a dangerous mutation, an animal with more cells living for longer should get more cancer. Within a species that roughly holds: taller people, who have more cells, have a slightly higher risk. Across species it fails completely. A blue whale has more than a thousand times as many cells as a person and can live for decades, yet whales and elephants are not riddled with tumours, while mice, small and short-lived, get cancer often. The puzzle is called Peto's paradox, after the epidemiologist Richard Peto, who pointed it out in the 1970s.
The answer seems to be that large animals evolved extra defences. Elephants carry about twenty copies of the gene for p53, against the single pair in humans, and their cells respond to DNA damage by destroying themselves far more readily than ours do; studies of zoo elephants suggest fewer than one in twenty die of cancer, against roughly one in five people. Whales appear to have extra or altered genes for DNA repair, and the long-lived naked mole rat fills its tissues with an unusually large sugary molecule that seems to stop cells growing when crowded. Researchers hope some of these tricks could one day be borrowed for medicine.
A vaccine that prevents a cancer
Most cancers cannot be prevented by a vaccine, but cervical cancer is a striking exception, because nearly all cases are caused by persistent infection with certain types of human papillomavirus, or HPV. Vaccines against the most dangerous HPV types were introduced in the late 2000s, and many countries now offer them to teenagers before they are likely to be exposed.
The effect has been dramatic. A study published in 2021 of the vaccination programme in England found that cervical cancer rates were around 87 per cent lower among women offered the vaccine at age twelve to thirteen than in earlier unvaccinated groups. Combined with screening, which finds abnormal cells before they become cancer, the results have led health bodies to set targets for eliminating cervical cancer as a public health problem.
The takeaway
Cancer is the uncontrolled growth of a cell's own descendants after mutations, accumulated over years from copying errors, chemicals, radiation or viruses, have switched on its accelerators and disabled its brakes, above all the p53 checkpoint. A tumour becomes lethal when its cells acquire the ability to spread and grow at distant sites, and it is fought with surgery, radiation and chemotherapy, and increasingly with drugs aimed at the specific broken protein and with therapies that release the immune system.