The Emperor of All Maladies: A Biography of Cancer (73 page)

Vogelstein was inspired by the observations made by George Papanicolaou and Oscar Auerbach in the 1950s. Both Papanicolaou and Auerbach, working on different cancers, had noted that cancer did not arise directly out of a normal cell. Instead, cancer often slouched toward
its birth, undergoing discrete, transitional stages between the fully normal and the frankly malignant cell. Decades before cervical cancer evolved into its fiercely invasive incarnation, whorls of noninvasive premalignant cells could be observed in the tissue, beginning their first steps in the grisly march toward cancer. (Identifying and eradicating this premalignant stage before the cancer spreads is the basis for the Pap smear.) Similarly, Auerbach had noted, premalignant cells were seen in smokers’ lungs long before lung cancer appeared. Colon cancer in humans also underwent graded and discrete changes in its progression, from a noninvasive premalignant lesion called an adenoma to the highly invasive terminal stage called an invasive carcinoma.

Vogelstein chose to study this progression in colon cancer. He collected samples from patients representing each of the stages of colon cancer. He then assembled a series of four human cancer genes—oncogenes and tumor suppressors—and assessed each stage of cancer in his samples for activations and inactivations of these four genes.
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Knowing the heterogeneity of every cancer, one might naively have presumed that every patient’s cancer possessed its own sequence of gene mutations and its unique set of mutated genes. But Vogelstein found a strikingly consistent pattern in his colon cancer samples: across many samples and many patients, the transitions in the stages of cancer were paralleled by the same transitions in genetic changes. Cancer cells did not activate or inactivate genes at random. Instead, the shift from a premalignant state to an invasive cancer could precisely be correlated with the activation and inactivation of genes in a strict and stereotypical sequence.

In 1988, in the
New England Journal of Medicine
, Vogelstein wrote: “
The four molecular alterations accumulated
in a fashion that paralleled the clinical progression of tumors.” He proposed, “Early in the neoplastic process one colonic cell appears to outgrow its companions to form a small, benign neoplasm. During the growth of [these] cells, a mutation in the
ras
gene . . . often occurs. Finally, a loss of tumor suppressor genes . . .
may be associated with the progression of adenoma to frank carcinoma.”

Since Vogelstein had preselected his list of four genes, he could not enumerate the total number of genes required for the march of cancer. (The technology available in 1988 would not permit such an analysis; he would need to wait two decades before that technology would become available.) But he had proved an important point, that such a discrete genetic march existed. Papanicolaou and Auerbach had described the pathological transition of cancer as a multistep process, starting with premalignancy and marching inexorably toward invasive cancer. Vogelstein showed that the
genetic
progression of cancer was also a multistep process.

This was a relief. In the decade between 1980 and 1990, proto-oncogenes and tumor suppressor genes had been discovered in such astonishing numbers in the human genome—at last count, about one hundred such genes—that their abundance raised a disturbing question: if the genome was so densely littered with such intemperate genes—genes waiting to push a cell toward cancer as if at the flick of a switch—then why was the human body not exploding with cancer every minute?

Cancer geneticists already knew two answers to this question. First, proto-oncogenes need to be activated through mutations, and mutations are rare events. Second, tumor suppressor genes need to be inactivated, but typically two copies exist of each tumor suppressor gene, and thus two independent mutations are needed to inactivate a tumor suppressor, an even rarer event. Vogelstein provided the third answer. Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer’s march was long and slow and proceeded though many mutations in many genes over many iterations. In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps.

While Bert Vogelstein was describing the slow march of cancer from one gene mutation to the next, cancer biologists were investigating the functions of these mutations. Cancer gene mutations, they knew, could succinctly be described in two categories: either activations of proto-oncogenes or inactivations of tumor suppressor genes. But although dysregulated cell division is the pathological hallmark of cancer, cancer cells do not merely divide; they migrate through the body, destroy other tissues, invade organs, and colonize distant sites. To understand the full syndrome of cancer, biologists would need to link gene mutations in cancer cells to the complex and multifaceted abnormal behavior
of these cells.

Genes encode proteins, and proteins often work like minuscule molecular switches, activating yet other proteins and inactivating others, turning molecular switches “on” and “off” inside a cell. Thus, a conceptual diagram can be drawn for any such protein: protein A turns B on, which turns C on and D off, which turns E on, and so forth. This molecular cascade is termed the signaling pathway for a protein. Such pathways are constantly active in cells, bringing signals in and signals out, thereby allowing a cell to function in its environment.

Proto-oncogenes and tumor suppressor genes, cancer biologists discovered, sit at the hubs of such signaling pathways. Ras, for instance, activates a protein called Mek. Mek in turn activates Erk, which, through several intermediary steps, ultimately accelerates cell division. This cascade of steps, called the Ras-Mek-Erk pathway—is tightly regulated in normal cells, thereby ensuring tightly regulated cell division. In cancer cells, activated “Ras” chronically and permanently activates Mek, which permanently activates Erk, resulting in uncontrolled cell division—pathological mitosis.

But the activated
ras
pathway (Ras
→
Mek
→
Erk) does not merely cause accelerated cell division; the pathway also intersects with other pathways to enable several other “behaviors” of cancer cells. At Children’s Hospital in Boston in the 1990s, the surgeon-scientist Judah Folkman demonstrated that certain activated signaling pathways within cancer cells,
ras
among them, could also induce neighboring blood vessels to grow.
A tumor could thus “acquire” its own blood supply
by insidiously inciting a network of blood vessels around itself and then growing, in grapelike clusters, around those vessels, a phenomenon that Folkman called tumor angiogenesis.

Folkman’s Harvard colleague Stan Korsmeyer
found other activated pathways in cancer cells, originating in mutated genes, that also blocked cell death, thus imbuing cancer cells with the capacity to resist death signals. Other pathways allowed cancer cells to acquire motility, the capacity to move from one tissue to another—initiating metastasis. Yet other gene cascades increased cell survival in hostile environments, such that cancer cells traveling through the bloodstream could invade other organs and not be rejected or destroyed in environments not designed for their survival.

Cancer, in short, was not merely genetic in its origin; it was genetic
in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

These gene cascades, notably, were perversions of signaling pathways used by the body under normal circumstances. The “motility genes” activated by cancer cells, for instance, are the very genes that normal cells use when they require movement through the body, such as when immunological cells need to move toward sites of infection. Tumor angiogenesis exploits the same pathways that are used when blood vessels are created to heal wounds. Nothing is invented; nothing is extraneous. Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own. Susan Sontag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves.

By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site.

In one cell in that clump an accidental mutation occurs in the
ras
gene. The mutation creates an activated version of
ras.
The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed—cancer’s primordial ancestor.

A decade passes. The small collection of
ras
-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of
ras
-mutated cells. A cell in this clump
acquires a second mutation in its genes, activating a second oncogene.

Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.

Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.

Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung.

The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs.

Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet
another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body—in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is seventy-six years old.