by Sam Kean
Why was the liver so hospitable to metastasis, while the spleen, which had similarities in blood supply, size, and proximity, seemed relatively resistant? As Paget probed deeper, he found that cancerous growth even favored particular sites within organ systems. Bones were a frequent site of metastasis in breast cancer—but not every bone was equally susceptible. “Who has ever seen the bones of the hands or the feet attacked by secondary cancer?” he asked. Paget coined the phrase “seed and soil” to describe the phenomenon. The seed was the cancer cell; the soil was the local ecosystem where it flourished, or failed to. Paget’s study concentrated on patterns of metastasis within a person’s body. The propensity of one organ to become colonized while another was spared seemed to depend on the nature or the location of the organ—on local ecologies. Yet the logic of the seed-and-soil model ultimately raises the question of global ecologies: why does one person’s body have susceptible niches and not another’s?
Paget’s way of framing the issue—metastasis as the result of a pathological relationship between a cancer cell and its environment—lay dormant for more than a century. There were exceptions. The pioneering metastasis researcher Isaiah J. Fidler, working at the National Cancer Institute during the 1970s and 1980s, started to study “cross-talk” between tissue and tumor. A tumor, Fidler showed, is made of a heterogeneous mixture of millions of cells, only a fraction of which are equipped to leave the primary tumor, form an exploitative alliance with the “soil” of another organ, and initiate metastasis. In the same period, Mina Bissell, working at the University of California, Berkeley, and then at the Lawrence Berkeley National Laboratory, began scrutinizing the microenvironments in which tumors formed—or didn’t—as she looked for factors that enabled or disabled the growth of cancer in various organs. Context, she found, was critical.
Yet oncology as a whole remained dominated by a simpler model. When I was a medical student in Boston, I spent an evening in a frigid deli on Boylston Street memorizing the list of bone-metastasizing cancers (breast, lung, thyroid, kidney, prostate) using the unsavory mnemonic “BLT with kosher pickle” and coming up with a mental image of how metastases might form. Cancer “disseminated” via blood vessels, “attacked” the organs, and began to sprout and flourish there. As I rotated through the cancer wards in the late 1990s, doctors reinforced this idea. “This tumor is invading the brain,” one surgeon murmured to another in an operating room. (By contrast, who ever said that the cold catches you?) Subject, verb, object: cancer was the autonomous actor, the aggressor, the mover. The hosts—the patients, their organs—were the hushed audience, the afflicted victims, the passive onlookers.
This language reflected an almost ontological commitment. It persisted even when research paradigms shifted. “Cancer is a genetic disease at its core,” the MIT cancer biologist Robert Weinberg says. For decades, accordingly, biologists have looked for gene mutations that enable some aspect of cancer cells’ aberrant growth, metabolism, regeneration, or behavior. In the late 1980s, a number of cancer biologists, Weinberg most prominently among them, threw themselves into finding such genes for metastasis—met genes, in effect. Might a breast-cancer cell, say, acquire a mutation that allowed it to unmoor itself from the breast and colonize the brain?
Despite a decades-long search, the met genes never materialized. “We looked and looked again, but we never found any,” Weinberg told me. Occasionally, mutations were detected in cancer metastases that were different from the primary tumor, but no mutations emerged as singular drivers of metastasis. Starting in the late 1990s, cancer geneticists tried another approach. Mutations in cancer cells don’t act in isolation; they can turn dozens, even hundreds, of other genes on and off. And those patterns of activation and repression can make an enormous difference—in the way that similar keyboards can produce wildly different sounds. (A caterpillar has the same genome as the butterfly it turns into, just as your liver cells have the same genome as your brain cells.) Instead of hunting for individual mutations, researchers looked for patterns of gene regulation—so-called gene-expression signatures. These patterns were used to develop predictive tests, which were rapidly shepherded into clinical trials.
For some variants of breast cancer, the tests turned out to be useful. Widely used gene-expression assays, such as MammaPrint and Oncotype DX, have helped doctors identify certain patients who are at low risk for metastatic spread and can safely skip chemotherapy. “We’ve been able to reduce the overuse of chemotherapy in about one-third of all patients in some subtypes of breast cancers,” Daniel Hayes said.
Hayes is also grateful for the kind of genetic tests that indicate which patients might benefit from a targeted therapy like Herceptin (those whose breast cancers produce high levels of the growth-factor receptor protein HER2) or from antiestrogen medications (those whose tumors have estrogen receptors). But, despite our advances in targeting tumor cells using genetic markers as guides, our efforts to predict whose cancers will become metastatic have advanced only slowly. The “whether me” question haunts the whole field. What the oncologist Harold Burstein calls “the uncertainty box” of chemotherapy has remained stubbornly closed.
In 2001, Joan Massagué, a cancer biologist at New York’s Memorial Sloan Kettering Cancer Center, came upon a scientific paper that radically changed his thinking about metastasis. Originally from Barcelona, Massagué—with his salt-and-pepper hair, his customary button-down shirt with an open collar—resembles a diplomat after embassy hours. He had spent years studying cell biology, elucidating mechanisms of gene regulation that might prime breast cells to travel to the bone instead of to the brain. Then came a crucial piece of evidence, buried in an obscure journal and published nearly three decades earlier. Researchers at the National Institutes of Health had implanted a sac of breast-cancer cells into the ovarian pedicle of a female rat. The cells grew to form a bean-sized tumor. The researchers then cannulated a large vein that was draining the tumor and siphoned blood from the vein every few hours in order to count the number of cancer cells that the tumor was shedding.
The results baffled the investigators. On average, they found, the tumor was sloughing off 20,000 cancer cells into every milliliter of blood—roughly 3 million cells per gram of tumor every 24 hours. In the course of a day, the tumor molted nearly a tenth of its weight. Later studies, performed with more sophisticated methods and with animal tumors that had arisen more “naturally,” confirmed that tumors continually shed cells into circulation. (The rate of shedding from localized human tumors is harder to study, but available research tends to confirm the general phenomenon.)
“We imagine metastasis as a going problem,” Massagué told me. “Mets go to the bone. Mets go to the brain.” He punctuated the air with his fingers at each verb, his face flushed with excitement. “And—yes, yes—going is important, because we need to find what allows cells to break away from the tumor and enter the blood and the lymph nodes. But if primary human tumors shed cells continually, and if every cell is capable of forming visible metastasis, then every patient should have countless visible metastatic deposits all over his or her body.” Anna Guzello’s breast tumor should have stippled her brain, bones, and liver with mets. Why, then, did she have no visible evidence of disease anywhere else in her body? The real conundrum wasn’t why metastases occur in some cancer patients but why metastases don’t occur in all of them.
“The only way I could explain the scarcity of metastasis,” Massagué said, “was to imagine that an enormous wave of cellular death or cellular dormancy must restrict metastasis. Either the cells shed by the tumor are killed, or they stop dividing, becoming dormant. When tumor cells enter the circulation, they must perish almost immediately, and in vast numbers. Only a few reach their destination organ, such as the brain or the bone.” Once they do, they face the additional problem of surviving in unfamiliar and possibly hostile terrain. Massagué inferred that those few survivors must lie in a state of dormancy. “A visible, clinical metastasis—the kind that we
can detect with CAT scans or MRIs—must only occur once a dormant cell has been reactivated and begins to divide,” he said. Malignancy wasn’t simply about cells spreading; it was also about staying—and flourishing—once they had done so.
In the spring of 2012, while Massagué and others were searching for sleeper cells, Gilbert Welch, an epidemiologist at Dartmouth, was preoccupied with a different problem: the unfulfilled promise of early detection. Early detection programs aimed to catch and eliminate cancers that were otherwise destined to become metastatic, but a huge ramp-up in screenings for certain cancers hadn’t yielded comparable benefits in the mortality statistics. Welch was trained as a statistician as well as a physician, and when he recites numbers and equations his voice rises to a booming pitch, as if he were a televangelist moonlighting as a math teacher. To illustrate an extreme version of the problem, Welch told me the story of an epidemic-that-wasn’t. In South Korea, starting about 15 years ago, doctors began to screen aggressively for thyroid cancer. Primary-care offices in Seoul were outfitted with small ultrasound devices, and doctors retrained themselves to catch the earliest signs of the disease. When a suspicious-looking nodule was found, it was biopsied. If the pathology report was positive, the patient’s thyroid gland was surgically removed.
The official incidence of thyroid cancer—in particular, a subtype termed papillary thyroid cancer—began to soar across the nation. By 2014, thyroid-cancer incidence was 15 times what it was in 1993, making it the most commonly diagnosed cancer in the country. It was as if a “tsunami of thyroid cancer,” in the words of one researcher, had suddenly hit. Billions of Korean wons were poured into treatment; tens of thousands of resected thyroids ended up in surgical buckets. Yet the rate at which people died from thyroid cancer remained unchanged.
What happened? It wasn’t medical error: observed under the microscope, the questionable nodules met the criteria for thyroid cancer. Rather, what the pathologists were finding wasn’t particularly pathological—these thyroid cancers had little propensity to cause illness. The patients had been not misdiagnosed but overdiagnosed; that is, cancers were identified that would never have produced clinical symptoms.
In 1985, pathologists in Finland assembled a group of 101 men and women who had died of unrelated causes—car accidents or heart attacks, say—and performed autopsies to determine how many harbored papillary thyroid cancer. They cut the thyroid glands into razor-thin sections, as if carving a hock of ham into prosciutto slices, and peered at the sections under a microscope. Astonishingly, they found thyroid cancer in more than a third of the glands inspected. A similar study regarding breast cancer—comparing breast cancer incidentally detectable at autopsy with the lifetime risk of dying of breast cancer—suggests that a hyperzealous early detection program might overdiagnose breast cancer with startling frequency, leading to needless interventions. Surveying the results of prostate-cancer screening, Welch calculated that 30 to 100 men would have to undergo unnecessary treatment—typically, surgery or radiation—for every life saved.
“The early detection of breast cancer via mammography saves women’s lives, although the benefit is modest,” Daniel Hayes told me. But equally important is the question of what to do with the tumor we’ve detected: can we learn how to identify those cancers that need to be treated systemically with chemotherapy or other interventions? “It’s not just early detection that we want to achieve,” Hayes went on. “It’s early prediction.”
For Welch, the fact that diagnoses of thyroid cancer or prostate cancer could soar without a corresponding effect on mortality rates was a warning: a little knowledge had turned out to be a dangerous thing. Cancer-screening campaigns had expanded the known reservoir of disease without telling us if, in any particular case, treatment was necessary. Early detection helped us with when and what but not with whether. And there was an element of mystery. Why did some cancers spread and kill patients, while many remained docile?
One day in March 2012, Welch flew to Washington to attend a conference on cancer metastasis. It was a gusty, gray morning—“the hotel was nondescript, the food unremarkable”—and Welch, dangling the requisite nametag on a forlorn lanyard, found himself in a room full of cancer biologists, feeling like an alien species. “I study patterns and trends in cancer in human populations,” he told me. “I take the 100,000-foot view of cancer. This meeting was full of metastasis biologists looking at cancer cells under the microscope. I couldn’t tell what any of this had to do with population trends in human cancer—or, for that matter, why I’d even come to this meeting.”
Then, coffee jolting in his hand, he saw a slide on the screen that made him sit up and take notice. It depicted the infestation of mussels in Lake Michigan. The speaker, Kenneth Pienta, an oncologist from the University of Michigan (and now at Johns Hopkins), had heard about the quagga crisis and been struck by the seeming parallels with cancer. Rather than viewing invasiveness as a quality intrinsic to a cancer, researchers needed to consider invasiveness as a pathological relationship between an organism and an environment. “Together, cancer cells and host cells form an ecosystem,” Pienta reminded the audience. “Initially, the cancer cells are an invasive species to a new niche or environment. Eventually, the cancer-cell–host-cell interactions create a new environment.” Ask not just what the cancer is doing to you, Pienta was saying. Ask what you are doing to the cancer.
By talking about cancer in ecological terms, Pienta was, in the tradition of Paget and Fidler, urging his colleagues to pay more attention to the soil. A woman with a primary tumor in her breast was caught in a pitched but silent battle. Oncologists had spent generations studying one possible outcome of that battle: when the woman lost, she succumbed to metastasis. But what happened when cancer lost the battle? Perhaps cancer cells tried to invade new niches but mainly perished en route, as a result of the resistance mounted by her immune system and other physiological challenges; perhaps the select few that, singly or in clusters, survived the expedition ended up languishing in forbidding tissue terrain, like seeds landing on a salt flat.
Welch was captivated. We had to be alert to the differences between the rampaging quagga mussel and the endangered purple-cat’s-paw mussel—but what about the differences between the Great Lakes and the Dnieper? Evidence suggested, for example, that most men with prostate cancer would never experience metastasis. What made others susceptible? The usual approach, Welch knew, would be to look for markers in their cancer cells—to find patterns of gene activation, say, that made some of them dangerous. And the characteristics of those cells were plainly crucial. Pienta was arguing, though, that this approach was far too narrow. At least part of the answer might lie in the ecological relationship between a cancer and its host—between seed and soil.
In 1992, an Australian high school teacher in his late fifties was diagnosed with melanoma. The malignancy began as a streak of black—a cancellation sign extending from his left armpit across the torso. A few weeks after the diagnosis, though, the borders of the tumor began to change. One edge turned gray; another shrank. “He had a classic spontaneous regression—typically a sign that the cancerous lesion was being controlled by the immune system,” David Adams, the man’s son, told me. The primary melanoma was surgically resected, and no metastasis was ever found. One of his father’s friends, also in his fifties, was not so lucky: by the time his primary melanoma had been discovered, his brain was sprinkled with visible mets.
David Adams went on to train as a geneticist and a physiologist in Sydney, before joining the Sanger Institute, in Cambridge, England. There he leads a group studying the biology of melanoma. Originally from Tamworth, a small outback town in New South Wales (“hot, flat farming country, right in the middle of Australia’s melanoma belt,” he says), Adams now lives 10,000 miles away, in a quaint English village, speaks with a mild Cantabrigian accent, and drives a gently distressed compact car to work. He has, in short, gone native—a matter of soil over seed, you might think—but he hasn’t forgotten
his father’s case; it’s what has driven his scientific career. What had made a melanoma regress in one host and turn aggressive in another? Adams knew of a strange series of melanoma cases, occasionally reported in the medical literature, involving donated kidneys. They fit a pattern. A patient—call him D.G.—is diagnosed with a melanoma and successfully treated with surgical resection. Years later, D.G., now deemed perfectly healthy, donates a kidney to a friend. The friend is prescribed routine immune suppressants to prevent the rejection of the kidney. A few weeks later, however, the recipient begins to sprout hundreds of black pinpricks of melanoma in the kidney. The melanoma, bizarrely, has come from D.G.’s cells. The donated kidney has to be removed. Meanwhile, the donor—like some Dorian Gray of transplantation—remains uncannily healthy, with no sign of melanoma in his body.
Here, too, Adams realized, the original host environment played a crucial role in restricting metastatic growth. The donor’s melanoma cells must have been sitting dormant in the donated kidney, akin to the phenomenon of dormancy that Massagué had found in mice. When the “soil” changed, and the dormant cells arrived in an immune-suppressed recipient, the cancer began to grow. “The immune response in the donor must have been restricting the metastatic cancer’s growth,” Adams told me.
In 2013, Adams began to conceive an ambitious experiment to identify cancer-suppressing host factors. “Just a few yards from my office, there is an animal vivarium filled with hundreds of genetically altered mouse strains,” he said. “Researchers were using these strains to study the effect of these gene variants on the heart, or on the nervous system. I thought I would ask a somewhat different question: if we implanted these strains with the same cancer, which strains would permit the metastases to grow, and which ones would suppress metastatic outgrowth?”
