Journal of the National Cancer Institute Advance Access originally published online on August 8, 2007
JNCI Journal of the National Cancer Institute 2007 99(16):1220-1221; doi:10.1093/jnci/djm124
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© Oxford University Press 2007.
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TRAVERSING THE BODY
Researchers Unravel How Metastatic Cancers Leave Home and Take Over Other Tissues
Like ancient Vikings, tumors send voyagers off from their malignant home to pillage and plunder other tissues in the body. The trips appear to follow a plan, since the same cancer types tend to travel to similar destination tissues in patient after patient.
But the itinerary of these metastatic cancer cells remains a mystery to oncologists and physicians, even though 90% of deaths from tumors are due to metastases. The questions abound: Not only why do they break off, but how, and why do they come to rest where they do? Unfortunately, the nature of metastases has made them traditionally harder to study than solid tumors. "The reason not a lot of studies are done on metastases is because it's something you have to do in vivo," says molecular biologist Yibin Kang, Ph.D., of Princeton University in New Jersey.
In the last half-dozen years, researchers have been making strides in getting metastatic cancer cells and the tissues they invade to spill their secrets. Gene expression arrays and imaging have helped scientists most recently. "One can now begin to deconstruct the metastatic process in discrete biological steps. That is very encouraging to the tumor biology community," says Joan Massagué, Ph.D., of Memorial Sloan-Kettering Cancer Center in New York. Finding the genes involved in metastasis means that researchers can develop new drugs that interfere with cancer's deadly spread.
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Schools of Thought
One of the earliest predominant hypotheses for why cancer cells go where they do was the "seed and soil" theory. Essentially, cancer cells were seeds that rooted around for an appropriate soil in which to grow. A challenge to this idea came in the late 1920s: Cancers spread through the bloodstream. Eventually, these two ideas melded into one: Seeds could be transported by the bloodstream, but they could take root only in tissues suited to their needs.
Today's tumor biologists are adding a new twist. The seeds must also express the correct subset of genes, their "signature," to be successful in their venture. Researchers are trying to understand the set of genes that make cells generally head out to new environs and specifically how they choose which tissue in which to grow. "If a patient had metastases in different organs, we are going to propose that for each organ, the tumor [cells] had to develop a different set of functions. Lung and bone environments are different, and the cells have used different sets of genes," Massagué says.
So these cells can establish a beachhead in another tissue only when they find the right spot to grow. "You can’t grow rubber tree plants in arctic tundra or cold-weather flowers in the tropics," says tumor biologist Danny Welch, Ph.D., of the University of Alabama at Birmingham. Different proteins line blood vessel walls like addresses on a house to indicate what kind of tissue exists beyond the vessel wall. Cells probably float around until they bump into the address that suits their needs, Welch says. A variety of protein addresses have been identified, such as some CAMs (cellular adhesion molecules).
According Welch, two major themes are emerging in the world of metastases genes. The first focuses on genes that control the metastatic cancer cell, and the second on the environments in which the cancer cells establish themselves. "Most of that work has been in breast cancer and melanoma. Some in prostate cancer. And that's largely because that's what we have the [animal] models for," he says. The signatures that allow the cells to leave their home tumor are thought to be found in some cancer cells from a primary tumor, but not all.
For example, Massagué's group used a cell line derived from one patient's metastatic breast cancer to find genes responsible for metastasizing cancer cells to the lung. First they injected these cells into mice. Some mice acquired lung metastases, which the team purified and reinjected into new mice. A second round of this resulted in a population of highly aggressive metastatic cells that attacked the lungs. Comparing the aggressive genes in the second-generation cells to those in the original tumor, the team found 18 genes that the metastatic cells cranked up, they reported in a 2005 study. A 2007 study of 639 breast cancer patients revealed that those18 genes could predict poor prognosis as effectively as determining the tumor's estrogen receptor status. "Those 18 genes, they really matter. These ones look hot," Massagué says. At least four of the genes had a tie to metastasis: "Those genes are in charge of allowing cells to form blood vessels so the cells can exit from circulation when they get to the lung," he says.
Other researchers are looking for genes that prevent rather than encourage metastases. Welch and others have found at least four genes whose activity prevents cancer cells from establishing themselves at other venues. In the late 1990s, for example, Welch's group overproduced a protein called KiSS-1 in the same breast cancer cell line. When injected into mice, KiSS-1 cut the metastatic potential of tumor cells by 95% compared with the cells that didn’t overproduce it. "[KiSS-1 cells] invade, they get in the blood and survive there and adhere to the blood vessels and crawl out and into tissues. But then they sit there dormant," Welch says. "Clinically, about 5–6 years after a tumor diagnosis, a patient is at risk for developing a wave of metastases because the cells have lain dormant and reawakened." He’d like to use his knowledge about these genes to "make cells dormant" for 5 or 10 years. "That's 5–10 years for the patient," he says.
Home Sweet Home
The environment the cells move to, sometimes referred to as their niche or tissue microenvironment, is also a current focus of research. "Cancer cells don’t exist in isolation," Welch says. Preliminary results with KiSS-1 suggest that the protein and others can change how the cancer cell responds to signals coming from outside the cell. For example, KiSS might tweak the signal induced by a growth factor in tissues, but research to determine how metastasis suppressor genes might do this is ongoing.
When prostate cancer cells try to invade lung tissue, a protein that resides on the surface of the cancer cell physically interacts with a protein on blood vessel cells, according to work from Kounosuke Watabe, Ph.D., at Southern Illinois University in 2006. This interaction shuts down the ability of the cancer cells to multiply in that location. Mice lacking a protein called DARC protruding from cells lining blood vessels acquired up to 10 times as many metastases as their DARC-carrying cousins.
Part of the difficulty of looking at metastases in traditional animal models is that the animals must be killed to determine what tissues the cancers have invaded. New technologies may help to illuminate how metastatic cells interact with their environment in real time. Princeton's Kang has engineered metastatic cells that produce a bioluminescent protein from fireflies. Unlike other fluorescent proteins, the intensity of the bioluminescence correlates with the size of metastases. More important, though, these cells can be seen in living animals. In forthcoming work, Kang's group looked at how metastatic cells and a compound called tumor growth factor 
(TGF-) encourages bone metastases. Kang has previously shown that bone releases TGF, what he calls a "major soil factor," to attract cells there.
Kang can put bioluminescing TGF- into mice whose metastatic cancer cells also bioluminesce and determine when and how bone-residing TGF- woos metastatic cells and how large the metastases become. "The exciting part is we can now control the activity of metastatic protein signaling in real time," he says. He is currently trying to determine whether TGF- is more important in bone metastases than in other tissues.
Remodeling the New Pad
Molecular biologist Evan Keller, D.V.M., Ph.D., of the University of Michigan–Ann Arbor, studies why two cancers that metastasize into the same tissue exhibit different characteristics once they’re there. When breast cancer spreads to bone, for example, the cancer cells break the bone down. On the other hand, metastatic prostate cancer cells stimulate bone growth. "From a global perspective, why is prostate cancer different when it spreads to bone?" Keller says.
The new bone growth isn’t of the same quality as the original bone, however. Work from his lab and others has shown that prostate cancer cells initially degrade bone, just as breast cancer cells do. But as the bone falls apart, it releases growth factors that modify the prostate cancer cells. The new prostate cancer cells start producing proteins that encourage haphazard bone growth. Armed with this information, clinicians have been focusing on preventing the bone breakdown in the first place.
Although research advances have started to pick apart the metastatic puzzle, researchers say they have a long way to go. Some biologists think new technologies and new approaches will help surmount the problem. "We’re in need of quantum leaps," Welch says.
But they agree that metastatic cancer is important to focus on. "Metastasis is one of the major hurdles to improving survival rate of cancers," Kang says. And so leaps in understanding can only help navigate the obstacle course of this disease.
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