Untangling the Roots of Cancer [Preview]

Recent evidence challenges long-held theories of how cells turn malignant--and suggests new ways to stop tumors before they spread

What causes cancer?

Tobacco smoke, most people would say. Probably too much alcohol, sunshine or grilled meat; infection with cervical papillomaviruses; asbestos. All have strong links to cancer, certainly. But they cannot be root causes. Much of the population is exposed to these carcinogens, yet only a tiny minority suffers dangerous tumors as a consequence.

A cause, by definition, leads invariably to its effect. The immediate cause of cancer must be some combination of insults and accidents that induces normal cells in a healthy human body to turn malignant, growing like weeds and sprouting in unnatural places.

At this level, the cause of cancer is not entirely a mystery. In fact, a decade ago many geneticists were confident that science was homing in on a final answer: cancer is the result of cumulative mutations that alter specific locations in a cell's DNA and thus change the particular proteins encoded by cancer-related genes at those spots. The mutations affect two kinds of cancer genes. The first are called tumor suppressors. They normally restrain cells' ability to divide, and mutations permanently disable the genes. The second variety, known as oncogenes, stimulate growth—in other words, cell division. Mutations lock oncogenes into an active state. Some researchers still take it as axiomatic that such growth-promoting changes to a small number of cancer genes are the initial event and root cause of every human cancer.

For the past few years, however, prominent oncologists have increasingly challenged that theory. No one questions that cancer is ultimately a disease of the DNA. But as biologists trace tumors to their roots, they have discovered many other abnormalities at work inside the nuclei of cells that, though not yet cancerous, are headed that way. Whole chromosomes, each containing 1,000 or more genes, are often lost or duplicated. Pieces of chromosomes are frequently scrambled, truncated or fused together. Chemical additions to the DNA, or to the histone proteins around which it coils, somehow silence important genes, but in a reversible process quite different from mutation. And scans of the genomes of malignant cells within tumors have found that they typically harbor myriad rare mutations rather than a handful of common genetic alterations.

The accumulating evidence has spawned new hypotheses that compete with the standard dogma to explain what changes come first and which aberrations matter most in the decadelong transformation of a cell and its descendants from well-behaved tissue to invasive tumor. The challengers dispute the dominant view of the disease as the product of a defined genetic state. They argue that it is more useful to think of cancer as the consequence of a chaotic process, a combination of Murphy's Law and Darwin's Law: anything that can go wrong will, and in a competitive environment, the most prolific variants will dominate.

Despite that shared underlying principle, the new theories make different predictions about what kind of treatments will work best. Some suggest that many cancers could be prevented altogether by better screening, changes in diet, and new drugs—or even by old drugs, such as aspirin. Other theories cast doubt on that hope.

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