Category: cancer

We aren’t particularly adept at predicting whether a specific patient’s cancer will become metastatic or not. Metastasis can seem “like a random act of violence,” Daniel Hayes, a breast oncologist at the University of Michigan, told me when we spoke at the asco meeting in Chicago. “Because we’re not very good at telling whether breast-cancer patients will have metastasis, we tend to treat them with chemotherapy as if they all have potential metastasis.” Only some fraction of patients who receive toxic chemotherapy will really benefit from it, but we don’t know which fraction. And so, unable to say whether any particular patient will benefit, we have no choice but to overtreat.

There are deep roots to the idea that a cancer’s metastases depend on local habitats. In 1889, an English doctor named Stephen Paget set out to understand cancer’s “primary growth and the situation of the secondary growths derived from it.” .... But when Paget collected the case files of seven hundred and thirty-five women who had died of breast cancer, he found a bizarre pattern of metastatic spread. The metastases didn’t appear to spread centrifugally; they appeared in discrete, anatomically distant sites. And the pattern of spread was far from random: cancers had a strange and strong preference for particular organs. Of the three hundred-odd metastases, Paget found two hundred and forty-one in the liver, seventeen in the spleen, and seventy in the lungs. Enormous, empty, uncolonized steppes—anatomical landmasses untouched by metastasis—stretched out in between.

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.

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..... 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-size 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 twenty thousand cancer cells into every millilitre of blood—roughly three million cells per gram of tumor every twenty-four 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.)

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.

.... 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.

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. .....Once we think of diseases in terms of ecosystems, then, we’re obliged to ask why someone didn’t get sick. 

 Cancer cells. Credit: Wikipedia, National Cancer Institute