August 15, 2006Scientists Begin to Grasp the StealthySpread of CancerBy LAURIE TARKANThe moment when a cancer begins to spread throughout thebody — metastasis — has always been the most dreadedturning point of the disease.Without metastasis, cancer would barely be a blip on thecollective consciousness. Fewer than 10 percent of cancerdeaths are caused by the primary tumor; the rest stem frommetastasis to vital sites like the lungs, the liver, the bonesand the brain.Though chemotherapy and other treatments havelengthened the lives of people with metastasized cancer, nodrugs have been specifically formulated to halt the process.That is because metastasis has remained something of amystery until the last five years or so.“In the last 30 years, we’ve learned all about identifyinggenes whose mutations initiate tumors,” said Dr. JoanMassagué, chairman of the Cancer Biology and GeneticsProgram at Memorial Sloan-Kettering Cancer Center in NewYork. But these advances, he added, did not explain themetastatic process.Now, knowledge of metastasis is beginning to accumulate tothe point that new therapies are entering the pipeline.“In terms of milestones or breakthroughs, most of them areabout to be made,” said Dr. Massagué.Dr. Patricia S. Steeg, chief of the women’s cancers section ofthe Laboratory of Molecular Pharmacology at the NationalCancer Institute, said she was optimistic for the first time.“The trickle is close, the first agents are in early clinicaltesting 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 discouragedresearch. To metastasize, cancer cells have to acquire severaldozen genetic alterations — in contrast with the handfultypically necessary to initiate a primary tumor, Dr. Massaguésaid. Further complicating matters, each case of metastasis— breast cancer that spreads to a lung, for instance, orprostate cancer that spreads to bone — is genetically andmolecularly different from the rest.Studying metastasis is expensive and time-consuming, and itrequires animal studies to track cancer cells that spread.Dr. Danny Welch, professor of pathology at the University ofAlabama at Birmingham, said scientists had avoided thisarea of inquiry. “There are under 100 people in the worldwhose labs focus on understanding more about howmetastasis works,” he said.Scientists have long had a rudimentary understanding of theprocess. Some have estimated that a million cancer cells aday break away from a tumor roughly two-fifths of an inch indiameter and that maybe one in hundreds of millions willthrive. If it weren’t so seldom, cancer would be far moredeadly.More than 80 percent of cancers arise in the inside lining oforgans. To metastasize, a cancer cell must break cellularbonds to dislodge itself, break down the mortar of theconnective tissue, change shape and sprout “legs” that canpull it through the densely packed tissue.After accomplishing this Houdini-like escape, the metastaticcell passes through a capillary into the blood stream, where itis tossed and tumbled and can be ripped apart by the sheerforce of circulation, or attacked by white blood cells.If the malignant cell survives, it clings to a tiny capillary atanother site, until it can eventually make its way out of thatcapillary into the tissue of a new organ.In foreign tissue, the cancer cell, now called amicrometastasis, faces a hostile environment. The liver, forinstance, is foreign territory to a breast cell. Some dieimmediately, others divide a few times, then die. Others staydormant.The surviving cancer cells regenerate and colonize, becominga macrometastasis that can be seen on diagnostic tests. Asthe metastasis grows, it becomes lethal by crowding outnormal cells and compromising the function of the organ.In recent years, scientists have begun to investigate each ofthese steps to identify the genes and their molecularproducts that drive the changes. Several emerging fields ofstudy have generated excitement among cancer researchers.One focuses on the notion that the environment of theinvaded organ, the microenvironment, plays a critical role inthe metastatic process.This is not an entirely novel idea. In 1889, the Britishpathologist Stephen Paget proposed the “seed and soilhypothesis,” which suggested that the cancer cell dependedon the secondary organ to thrive.Today, it is well understood that an organ has to becomesomewhat receptive to the tumor. The more welcoming it isand the fewer hurdles it puts up, the easier it is for a cancerto survive. This theory partly explains why certain primarycancers prefer to spread to certain other organs. Forexample, breast cancers metastasize to the brain, liver, bonesand lungs; prostate cancers prefer the bones, and coloncarcinomas often metastasize to the liver.“We’ve been focused on the seed for a long time, and we’renow starting to understand more about the soil and theinteraction between the seed and the soil,” said Dr. Lynn M.Matrisian, chairman of cancer biology studies at VanderbiltUniversity.“In my mind, the real opportunity comes fromunderstanding what makes a certain organ receptive to ametastatic cell growing there versus not receptive,” Dr.Matrisian said.Researchers are looking at a number of events that occur inthe microenvironment that give a cancer cell a leg up as soonas it arrives. These changes involve both normal cells thatreside in that tissue and the body’s roaming immune cells.“The tumor cells co-opt these cells to act in a way that’sconducive for the growth of the metastasis,” Dr. Massaguésaid.There is evidence, for example, that a type of white bloodcell, the macrophage, may help initiate colonization. It wasonce thought that high numbers of macrophages found inmetastatic cancer colonies were there to do battle with thecancer. Now it is believed that they somehow promotefactors that help tumors progress. Other normal cells arebelieved to make enzymes that loosen the cellular structureof the new host organ, making room for tumor cells toproliferate.Another example comes from the understanding of bonemetastasis. Breast cancer cells are known to activate normalcells called osteoclasts that break down bone. Bone is adynamic tissue constantly being broken down and rebuilt.But when bone is degraded, it releases growth factors thatincidentally fuel cancer.Many people with bone metastasis are now being treatedwith a class of