The moment when a cancer begins to spread throughout the body — metastasis — has always been the most dreaded turning point of the disease.
Without metastasis, cancer would barely be a blip on the collective consciousness. Fewer than 10 percent of cancer deaths are caused by the primary tumor; the rest stem from metastasis to vital sites like the lungs, the liver, the bones and the brain.
Though chemotherapy and other treatments have lengthened the lives of people with metastasized cancer, no drugs have been specifically formulated to halt the process. That is because metastasis has remained something of a mystery until the last five years or so.
“In the last 30 years, we’ve learned all about identifying genes whose mutations initiate tumors,” said Dr. Joan Massagué, chairman of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York. But these advances, he added, did not explain the metastatic process.
Now, knowledge of metastasis is beginning to accumulate to the point that new therapies are entering the pipeline.
“In terms of milestones or breakthroughs, most of them are about to be made,” said Dr. Massagué.
Dr. Patricia S. Steeg, chief of the women’s cancers section of the Laboratory of Molecular Pharmacology at the National Cancer Institute, said she was optimistic for the first time. “The trickle is close, the first agents are in early clinical testing or will be soon,” she said. “I’m very enthusiastic, much more than I was five years ago.”
The complexity of metastasis may well have discouraged research. To metastasize, cancer cells have to acquire several dozen genetic alterations — in contrast with the handful typically necessary to initiate a primary tumor, Dr. Massagué said. Further complicating matters, each case of metastasis — breast cancer that spreads to a lung, for instance, or prostate cancer that spreads to bone — is genetically and molecularly different from the rest.
Studying metastasis is expensive and time-consuming, and it requires animal studies to track cancer cells that spread.
Dr. Danny Welch, professor of pathology at the University of Alabama at Birmingham, said scientists had avoided this area of inquiry. “There are under 100 people in the world whose labs focus on understanding more about how metastasis works,” he said.
Scientists have long had a rudimentary understanding of the process. Some have estimated that a million cancer cells a day break away from a tumor roughly two-fifths of an inch in diameter and that maybe one in hundreds of millions will thrive. If it weren’t so seldom, cancer would be far more deadly.
More than 80 percent of cancers arise in the inside lining of organs. To metastasize, a cancer cell must break cellular bonds to dislodge itself, break down the mortar of the connective tissue, change shape and sprout “legs” that can pull it through the densely packed tissue.
After accomplishing this Houdini-like escape, the metastatic cell passes through a capillary into the blood stream, where it is tossed and tumbled and can be ripped apart by the sheer force of circulation, or attacked by white blood cells.
If the malignant cell survives, it clings to a tiny capillary at another site, until it can eventually make its way out of that capillary into the tissue of a new organ.
In foreign tissue, the cancer cell, now called a micrometastasis, faces a hostile environment. The liver, for instance, is foreign territory to a breast cell. Some die immediately, others divide a few times, then die. Others stay dormant.
The surviving cancer cells regenerate and colonize, becoming a macrometastasis that can be seen on diagnostic tests. As the metastasis grows, it becomes lethal by crowding out normal cells and compromising the function of the organ.
In recent years, scientists have begun to investigate each of these steps to identify the genes and their molecular products that drive the changes. Several emerging fields of study have generated excitement among cancer researchers.
One focuses on the notion that the environment of the invaded organ, the microenvironment, plays a critical role in the metastatic process.
This is not an entirely novel idea. In 1889, the British pathologist Stephen Paget proposed the “seed and soil hypothesis,” which suggested that the cancer cell depended on the secondary organ to thrive.
Today, it is well understood that an organ has to become somewhat receptive to the tumor. The more welcoming it is and the fewer hurdles it puts up, the easier it is for a cancer to survive. This theory partly explains why certain primary cancers prefer to spread to certain other organs. For example, breast cancers metastasize to the brain, liver, bones and lungs; prostate cancers prefer the bones, and colon carcinomas often metastasize to the liver.
“We’ve been focused on the seed for a long time, and we’re now starting to understand more about the soil and the interaction between the seed and the soil,” said Dr. Lynn M. Matrisian, chairman of cancer biology studies at Vanderbilt University.
“In my mind, the real opportunity comes from understanding what makes a certain organ receptive to a metastatic cell growing there versus not receptive,” Dr. Matrisian said.
Researchers are looking at a number of events that occur in the microenvironment that give a cancer cell a leg up as soon as it arrives. These changes involve both normal cells that reside in that tissue and the body’s roaming immune cells.
“The tumor cells co-opt these cells to act in a way that’s conducive for the growth of the metastasis,” Dr. Massagué said.
There is evidence, for example, that a type of white blood cell, the macrophage, may help initiate colonization. It was once thought that high numbers of macrophages found in metastatic cancer colonies were there to do battle with the cancer. Now it is believed that they somehow promote factors that help tumors progress.[This makes the counter-intuitive findings of #msg-12665642 easier to fathom.] Other normal cells are believed to make enzymes that loosen the cellular structure of the new host organ, making room for tumor cells to proliferate.
Another example comes from the understanding of bone metastasis. Breast cancer cells are known to activate normal cells called osteoclasts that break down bone. Bone is a dynamic tissue constantly being broken down and rebuilt. But when bone is degraded, it releases growth factors that incidentally fuel cancer.
Many people with bone metastasis are now being treated with a class of osteoporosis drugs known as bisphosphonates that inhibit osteoclasts[e.g. NVS’ Zometa]. The idea is to prevent the breakdown of bone, and to interrupt the vicious cycle.
Taking the microenvironment theory a step further, some researchers are looking into differences in genetic makeup that can make one person more — or less — tumor-friendly than another. This could lead to a simple blood test to predict who is at risk for metastasis. The goal would be more customized treatment, and those at high risk would be treated more aggressively. Those unlikely to progress would avoid unnecessary and toxic treatments.
Dr. Kent Hunter, an investigator at the Laboratory of Population Genetics at the National Cancer Institute, recently performed a breakthrough study in mice, which provided evidence that the DNA of an organism plays an important role in determining the risk of cancer spreading.
Dr. Hunter bred a strain of mice susceptible to metastasis with about 30 other strains of mice, and found that the offspring had varying rates of metastasis.
“Since these animals are all getting the same oncogene by breeding, the most likely explanation is that the changes are due to the differences in the genotype or genetic background of the mouse,” Dr. Hunter said.
In an epidemiological study of 300 women with breast cancer from Orange County, Calif., Dr. Hunter identified two genes that were associated with an increased risk of metastasis, though a large number of genes are probably involved in a person’s risk.
Another camp of researchers is looking at cancer cells for genes that can set off a whole set of steps, the so-called master regulators.
A major question is how cancer cells seem clever enough to succeed in the many steps necessary to metastasize. Dr. Robert Weinberg, a professor of biology at the Massachusetts Institute of Technology, is a leading proponent of a contested theory suggesting that a tumor cell turns on an embryonic program that allows a cancer cell to relocate.
“Over the last five years, it has become apparent that cancer cells don’t cobble together all these different talents, but they resurrect a previously latent behavioral program,” Dr. Weinberg said.
He argues that a program, called the epithelial-mesenchymal transition, or E.M.T, is turned on in embryonic cells, allowing them to move to different parts of the body where they set up camp and build different types of tissue. According to Dr. Weinberg, these programs are turned off after embryonic development, but they are sometimes briefly turned on in wound-healing to build new tissue.
“Cancer cells opportunistically resort to turning on these programs, and in so doing, acquire all the traits that permit them to disseminate through the body,” Dr. Weinberg said. “What remains unclear is whether or not all malignant carcinoma cells must undergo an E.M.T. in order to invade and metastasize.”
Dr. Welch of Alabama added, “The problem is experimentally proving there is a turning on of E.M.T. and then a turning off of E.M.T. when the cell lands at the distant site.”
Others are looking at cancer stem cells[#msg-11785699]. Adult stem cells have the ability to renew themselves and generate new cells, but they can also become cancerous. Some experts believe that cancer stem cells are at the core of every metastasis. This would help explain why millions of cells can reach distant organs, but only a select few — presumably those with stem cell capacities — can initiate a tumor and colonize.
To date, cancer stem cells have been isolated from a small number of tumor types, and more research is needed to elucidate whether stem cells initiate metastases and where and how they acquire their renewal capacities.
Most experts are looking at smaller pieces of the puzzle, many of them involving colonization, the final stage of metastasis. Upon diagnosis of cancer, experts suspect that many people already have micrometastases throughout their body. “The horse is out of the barn,” Dr. Welch said.
Because colonization is the least efficient step in the spread of cancer, it seems like the Achilles’ heel. A vast majority of cells that land in a distant tissue never succeed in growing and forming a macroscopic metastasis, Dr. Weinberg emphasized.
A number of laboratories have identified more than a dozen metastatic suppressor genes, which prevent micrometastases from colonizing but do not affect primary tumors. In metastatic cells, these genes — including NM23, Kiss1, MKK4, and RhoGDI2 — are either defective or inactive.
In several studies of mice, researchers have repaired defective metastatic suppressor genes and found that the tumor cells spread but did not colonize. In epidemiological studies, some of these genes that have been identified have been shown to be predictive of patient survival and metastasis, Dr. Welch said. Labs are now beginning to test agents that can activate the gene or repair it.
Other researchers are focusing on trying to halt the development of blood vessels that feed the micrometastasis in the process of angiogenesis. One of the first things a micrometastatic cell must do to thrive is call in new blood vessels, said Dr. Matrisian of Vanderbilt.
Drugs that inhibit angiogenesis have not proved that successful when used alone[e.g. Avastin], but they appear to have lengthened some lives when combined with chemotherapy, said Dr. Lee M. Ellis, professor of surgery and cancer biology at the M. D. Anderson Cancer Center in Houston.
Underlying these advances has been the shift in the understanding of metastasis — as many different processes rather than one simple mechanism, and different in each type of cancer. Each metastasis needs to be addressed separately.
“There are commonalities, from tissue to tissue, but what we’re finding, unfortunately, is that we need to develop therapies for each specific site,” said Dr. Steeg, of the cancer institute’s Center for Cancer Research.
“We used to think we only needed one pipeline to metastasis,” she said. “Pharmaceutical companies now realize that they have to look at subsets of cancer, rather than at all of breast cancer.”
“One advance can save many lives, but it’s only one bite,” Dr. Massagué, the Sloan-Kettering researcher, added, “because the next tumor type forming metastasis in the next organ needs to be addressed.” <<
Stem cells -- the master cells that give rise to all the blood and tissue in the body -- may also be responsible for tumors, according to two separate studies published on Sunday. Canadian and Italian researchers both found that specialized colon cancer stem cells appeared to be the sources of colon cancer tumors in mice.
Their findings, published in the journal Nature, support the idea that future cancer treatments will have to home in on cancer stem cells. Similar findings have been seen for leukemia, breast and brain cancers, but the two studies are the first to show cancer stem cells are also responsible for colon tumors.
"Colon cancer is one of the best-understood neoplasms (tumors) from a genetic perspective, yet it remains the second most common cause of cancer-related death (in Canada), indicating that some of its cancer cells are not eradicated by current therapies," John Dick of University Health Network in Toronto and colleagues wrote in their report.
They implanted human colon cancer cells into mice with a deficient immune system -- a standard way of studying cancer. Only certain cells, those with a protein on the surface called CD133, were able to initiate a new tumor. CD133 had previously been implicated in brain and prostate cancers.
In a second study, Ruggero De Maria of the Istituto Superiore di Sanita in Rome and colleagues got the same CD133 cells to start tumors when injected under the skin of immune-deficient mice.
"These studies demonstrate that a small population of colon cancer cells, distinct from those that make up the bulk of a tumor, initiate tumor growth," Nature said in a statement.
It may be possible to design drugs that attack only those cells, and thus treat colon cancer in a way that better affects the tumors without hurting healthy cells, the researchers said. <<
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