Cancer is a chilling ghost of conflict within an individual. A single cell opts out of the body's centralized control and proliferates like a bacterium. At a molecular level, the sequence of events is one of the most graphic illustrations of natural selection at work. Let's consider briefly what happens.
Cancer is usually, but not always, the result of genetic mutations. A single mutation is rarely enough. Typically, a cell must accumulate eight to ten mutations in rather specific genes before it can transform into a malignant cell, whereupon the transformed cell puts its own interests before those of the body. Genetic mutations tend to accumulate at random as we grow older, but it takes a particular combination to cause cancer: mostly the mutations must be in two sets of genes known as oncogenes and tumour-suppressor genes. Both sets code for proteins that control the normal 'cell cycle'—the way in which cells proliferate or die in response to signals from elsewhere in the body. The products of oncogenes normally signal a cell to divide in response to a particular stimulus (for example, to replace dead cells after an infection) but in cancer they get stuck in the 'on' position. Conversely, the products of tumour suppressor genes normally act as a brake on uncontrolled cell division: they countermand the signals for proliferation, making cells quiescent, or forcing them to commit suicide instead. In cancer, they tend to get stuck in the 'off' position. There are numerous checks and balances in cells, which is why it takes an average of eight to ten particular mutations before a cell transforms into a cancer cell. People with a genetic predisposition to cancer may inherit some of these mutations from their parents, leaving them with a lower threshold of 'new' mutations that must accumulate before the onset of cancer.
Transformed cells no longer respond normally to the body's instructions. As they proliferate, they form into a tumour. Yet there is still a big distinction between a benign growth and a malignant tumour: many other changes still have to take place for a cancer to spread. First of all, to grow larger than a couple of millimetres across, the tumour requires sustenance. Slow absorption of nutrients across the surface of the tumour is no longer enough—the tumour cells need an internal blood supply. To acquire a blood supply, they need to produce the right chemical messengers (or growth factors) in appropriate quantities to stimulate the growth of new blood vessels into the tumour. Further growth requires digestion of the surrounding tissues, giving the tumour space to invade: the cells need to spray potent enzymes that break down the tissue structure. Perhaps the most feared step is the leap to remote sites elsewhere in the body—metastasis. The properties required are opposing and specific. Cells must be slippery enough to escape the clutches of the tumour, and yet sticky enough to bind to the walls of blood vessels elsewhere in the body. They must be able to evade the attentions of the immune system during their passage through the blood or lymph system, often by 'sheltering' in a clump of cells that bind together despite their slipperiness. On arrival, the cells must be able to bore their way through the vessel walls, into the safe haven of the tissue behind—but then stop there. And throughout this hazardous solo journey they must retain their ability to proliferate, to found a cancerous outpost in the new continent of a different organ.
Luckily very few cells come equipped with the dialectical qualities needed to cause metastatic cancer. Yet few of us are untouched by cancer, if not ourselves, then our family, relatives, and friends. How, then, do cells acquire all the properties needed? The answer is that cancer cells evolve by natural selection. In the course of our lifetime, cells acquire hundreds of mutations, some of which may just happen to affect the oncogenes and tumour-suppressor genes that control the cell cycle. If a single cell is freed from the shackles that normally prohibit its proliferation, it proliferates. Soon it is not a single cell but a colony of cells, all of which are busily picking up new mutations. Many of these mutations are neutral, others are detrimental to the cells, but in time a few will cause a single cell to take the next step down the road to malignancy, then the next, and the next. Each time, the descendents proliferate: what had been a singular mutant becomes a heaving population, until this, too, is displaced by another single cell adapted to the next step. In the space of a few years, even a few months, the body becomes riddled with cancer. The cancer cells have no prospects—they are doomed to die as surely as we are. They simply do what they must, grow and change, a progression dictated by the inexorable blind logic of variation and selection.
What is the unit of selection in cancer, the gene or the cell? As we saw with bacteria, it makes more sense to think of the cells themselves as the selfish unit. The cells do not replicate by sex, but in the manner of bacteria, by asexual replication. The genes may change faster than the phenotype of the cell, which at least for a period retains many aspects of its provenance, including its appearance down the microscope. Even metastatic cancers betray their origins: if we scrutinize a tumour in the lung, it is usually possible to tell whether it is a 'primary' tumour, derived from the lung cells, or a 'secondary' tumour, a metastatic outpost of cells from a distant tissue such as the breast. We know because they still retain some atavistic traits of 'breast' cells, such as hormone production. At the same time, cancer cells are notorious for their genetic instability: chromosomes are lost, or broken, or cobbled together in wild rearrangements. So while the cells retain a semblance of their former appearance, their genes are scrambled out of recognition by mutations and rearrangements. If there is a 'selfish' evolutionary unit, surely it is the cell, which leaps all hurdles in its way until finally killing its master, a course as heavily laden with fate as that of Macbeth.
In cancer, the word 'selfish' rings hollow. There is no sense in which a malignant tumour is making a bid for freedom—it is simply a ghost in the machine, a pointless reversion to an earlier type, which ruled before the evolution of the 'individual'—that of cells doing their own thing. In this sense, cancer gives a dull and empty sense of the sheer meaninglessness of evolution. Cells replicate, and the cells that replicate best leave the most descendants. That's it. It's hard to think of any deeper meaning for cancer: it is mindless mechanics and no more. This contrasts with that other revealing view of evolution in microcosm, bacterial infection, where for all the grinding levers of bacterial replication there is still a strong whiff of purpose: we may find infections abhorrent, but we do accept that bacteria have a point—a life cycle, a future, an 'objective'. They're not doomed, but go on to infect another individual. (Of course, this distinction is in itself imaginary—neither bacteria nor cancer cells have any 'purpose'. However, cancer is a useful example, for it is plain that cancer cells are not equipped to outlive the body, and so the futility of their short-term success in self-replication is transparent.)
If cancer has no meaning, it does at least illustrate the obstacles that must be overcome to forge an individual. If today we still succumb to the lawlessness of cancer, what hope had the first individuals? In those days of looser associations, deserters had the same chance as bacteria of making it alone: desertion was not futile. How did the first individuals quell the strong tendency of their own cells to rebel? It seems they did so in the same way that we do today: they killed the transgressors via a mechanism known as programmed cell death, or apoptosis—they forced the dissident cells to commit suicide. Apoptosis exists even in cells that spend part of the time as independent free-living cells, and part of the time in colonies, begging the question: how and why did apoptosis evolve in single-celled organisms? Why would a potentially independent cell 'agree' to kill itself?
Much of our understanding of apoptosis comes from the study of its role in cancer. The more we learn, the more we appreciate that mitochondria play the title role in apoptosis. And as we trace our way back through evolutionary time, it emerges that apoptosis evolved out of the manipulative campaigns between mitochondria and their host cells in the first eukaryotes—at a time when colonies were far from the rule.
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