For much of the 20th century, a diagnosis of cancer terrified many who received it. Today, after some four decades of research progress in cancer detection, control, and treatment, the term that should cause more concern than "cancer" is "metastasis." Many oncologists agree that metastasis, not the primary tumor, is what kills most people who die from the disease.

"By the time we see patients in a clinic, the metastatic cells have often already spread," says Dr. Kent Hunter, chairperson of the Metastasis Working Group in NCI's Center for Cancer Research (CCR). Unfortunately, currently available imaging technologies cannot detect very small lesions or single metastatic tumor cells. Improved patient survival after application of adjuvant therapy, however, is thought to be due to successful targeting of these subclinical micrometastases.

The metastatic cell has been called the decathlete of tumor cells, says Dr. Hunter, because it must succeed at a succession of different tasks. It has to invade the circulating blood or lymph vessels, avoid attack by the immune system, survive a lack of nutrition and cell-to-cell contact, resist shear forces as it travels, stop at a likely spot, get back into adjacent tissue, and finally establish the blood supply needed to proliferate at this new site.

Many cells begin this journey, though only a few survive it. In theory, the sequential process could be thwarted at any point. However, since tumor dissemination is often an early event, the most likely points of clinical intervention are at the end of the metastatic cascade. "You don't want to target an earlier step and find out the horse has already left the barn," says Dr. Hunter.

"Metastatic cells may be quite susceptible to new treatments early after their arrival at secondary sites and as they begin to proliferate," says Dr. Chand Khanna, head of the Tumor Metastases Section in CCR's Pediatric Oncology Branch. Dr. Khanna and others have been working on antimetastasis approaches based on the role of a cytoskeleton protein called ezrin that contributes to many steps in the metastatic cascade.

"Ezrin is the ERM (ezrin-radixin-moesin) protein about which we know the most," says Dr. Khanna. It sits at the cell membrane and coordinates signals about what's happening outside the cell through the interior structure (the cytoskeleton), resulting in an appropriate cellular response.

Ezrin first emerged from mouse model experiments by Dr. Khanna and Dr. Glenn Merlino, chief of CCR's Laboratory of Cancer Biology and Genetics, conducted a few years ago using a series of osteosarcoma and rhabdomyosarcoma cell lines. "When we isolated the genes involved, ezrin popped out as a player in nearly all of the cell lines that were highly metastatic, but was barely expressed in lines that were poorly metastatic." If ezrin expression proves crucial to metastasis, suppressing it should not be too difficult, and may yield a therapeutic clinical strategy.

CCR Scientific Director for Clinical Research Dr. Lee Helman became very interested because he sees many patients in the Pediatric Oncology Branch with both of these cancers. Osteosarcoma is the most common bone tumor among children - less than 20 percent of patients with metastases will be cured.

He and Dr. Khanna wondered if the ezrin expression pattern seen in the mouse models could be found in people. They obtained tumor tissue from dozens of pediatric osteosarcoma patients and the data were clear. "Ezrin was more plentiful in the patients whose disease was highly metastatic compared with those that were not. Understanding the connections and pathways that include ezrin may be a major therapeutic opportunity in a disease we really want to go after," says Dr. Helman.

Dr. Patricia Steeg, head of the Women's Cancers Section in CCR's Laboratory of Molecular Pharmacology, is also unraveling the mechanics of metastasis. Her discovery of Nm23, the first metastasis suppressor gene, pointed the way to a dozen others and opened up a new class of experimental models, leading to a translational strategy. "We're looking at a compound to elevate Nm23 in micrometastatic tumor cells," she explains, with the hope of interfering with colonization in high-risk cancer patients.

— Addison Greenwood