Flesh of our Own Flesh

In which we learn that cancer is more than 200 different diseases, but they all share some common characteristics – the most important being that, if p53 is functioning properly, a cell cannot turn malignant.

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Tumours destroy man in a unique and appalling way, as flesh of his own flesh which has somehow been rendered proliferative, rampant, predatory and ungovernable.

Peyton Rous

'The question that's obsessed me for the whole of my career is: why is cancer so rare?' Gerard Evan, a professor of molecular biology at the University of California, San Francisco, and Cambridge, England, pauses to let his comment sink in. He knows it will startle me, for the statistics most commonly quoted in the media paint a bleak picture: that one in three of us will be diagnosed with cancer at some point in our lives and one in four of us will die of the disease. But Evan, talking to me in his office in the Sanger Building in a leafy corner of Cambridge about his years of research at the most fundamental level of the genes, is looking at cancer from the viewpoint of the cells, not of the whole human being. It takes just one rogue cell which has lost its normal regulatory machinery and run haywire to trigger cancer, yet billions upon billions of cells in our bodies that are growing and replicating themselves all the time do so typically for 50, 60 years or more without producing a tumour. And in two in three of us they never do. 'I mean, if you were doing the lottery you'd never gamble on this!' continues Evan. 'Cancers do arise, but clearly we've evolved amazingly elaborate and effective mechanisms to restrict the spontaneous evolution of autonomous cells within our bodies. And even though we bomb ourselves with mutagens and carcinogens and do all sorts of things we shouldn't do, still most people die of heart disease; they don't die of cancer.'

A measure of just how resistant our cells are to corruption is the fact that a goodly chunk of our DNA – nature's instruction manual for building our bodies – can be traced back to the original single- celled organism known as the 'last universal common ancestor' of all life on earth (often referred to by the acronym LUCA), whose existence was first proposed by Charles Darwin in his book On the Origin of Species, published in 1859. In other words, some of our genes are more than 3.5 million years old and have been passed down faithfully from one generation to the next over unimaginable eons of time.

The term 'cancer' represents not one but a collection of around 200 different diseases which share this common characteristic: they all originate from a single cell that has become corrupted. The great majority of cancers – well over 80 per cent – are carcinomas, which means they are in the epithelial cells that form the outer membranes of all the organs, tubes and cavities in our bodies, and include our skin. The connective tissue, which provides the structural framework for our bodies, and support and packaging for the other tissues and organs – it includes, for example, bone, cartilage, fibrous tissue such as tendons and ligaments, collagen and fatty tissue – appears extremely resistant to turning malignant. Sarcomas, which are cancers of the connective tissue, account for only about one in a hundred cases.

No one yet knows the reason for this bias, though speculation is intense. Could it be that epithelial cells tend to divide more often than connective tissue cells and the opportunity for mutation is much greater? Our skin, for instance, has an intense programme of self-renewal with cells at the base layer dividing and undergoing processes of differentiation and maturation as they push up towards the surface, where they are eventually sloughed off (that's what causes the tidemark around the bathtub). The lining of the gut, too, is constantly renewing itself, and the sloughed cells are excreted. However, an argument against high rates of proliferation being the main reason why epithelial cells are at greatest risk of malignancy is the fact that some of the most cancer- prone epithelial cells are not ones that divide most frequently. Some suggest that it is because epithelial cells are a first line of defence against the outside world and are more likely to come into contact with cancer- causing agents. But this argument too has weaknesses, since epithelial and connective tissue cells are equally exposed to carcinogens in some organs, notably the prostate, yet the epithelial cells are the more vulnerable.

Looking for answers to this conundrum, one lab took samples of healthy breast tissue, teased apart connective tissue cells from epithelial cells and watched what happened when they attacked them with chemical carcinogens in their Petri dishes. To their surprise, they saw that the two cell types reacted completely differently, though they still don't know exactly how or why. That's the Holy Grail, as it might point to chinks in cancer's armour as targets for new drugs.

Tumours typically arise from the pool of stem cells in a tissue that are responsible for the repair and replacement of cells as part of the routine maintenance of our bodies. It can take years, even decades, for a rogue cell to grow into a tumour that is detectable. This is because it depends on progressive breakdown of the cellular machinery through the mutation and/or loss of crucial genes that regulate growth, replication, repair and timely death of cells – mutations that occur independently and, crucially, don't result in the cell being eliminated, which is the normal fate of damaged cells. The growing tumour is parasitic: it competes with the normal cells around it for nutrients and oxygen, and it can't grow much beyond 1–2mm (1/25th–1/12th of an inch) in diameter unless it develops its own blood supply.

What distinguishes a malignant tumour from a benign one is the former's ability to spread – to send out microscopic shoots that penetrate the walls and invade neighbouring tissue, and to seed itself in distant sites from breakaway cells carried in the bloodstream or lymph system. Blood-borne dissemination is particularly efficient at spreading cancer, with the blood depositing its cargo of delinquent cells along natural drainage sites, most commonly the liver and...