A team of researchers at the National Cancer Institute (NCI), using a mouse model, have uncovered a novel protein interaction that promotes the spread of cancer cells (a process known as metastasis) in a class of tumors collectively called sarcomas. In doing so, they have found the first instance in which the modification and destruction of a protein, rather than a failure to make the protein, drives the spread of cancer. The findings are published in the December 2007 issue of Nature Medicine.

"These results add an entirely new perspective to our understanding of metastasis, and highlight the importance of studying mechanisms beyond gene expression in defining and addressing the reasons for cancer progression," said NCI Director John E. Niederhuber, M.D.

To metastasize, cancer cells must escape the original tumor, enter and exit the bloodstream or lymphatic system, and successfully colonize a new target organ or tissue. These steps require the activation and/or deactivation of numerous genes that play a variety of roles (e.g., cell migration, cell signaling, and adhesion).

Research into the root causes of metastasis has traditionally focused on genetic or genomic changes, such as the loss of genes that inhibit metastasis or the overexpression of genes that promote it. The NCI team from the Center for Cancer Research (CCR), led by Allan Weissman, M.D., chief of the Laboratory of Protein Dynamics and Signaling, and by Chand Khanna, Ph.D., head, of the Tumor and Metastasis Biology Section in the Pediatric Oncology Branch, took a different approach in this study. Instead of examining gene-based mechanisms, the NCI team focused on chemical changes that are made to protein products after they have been translated from their genes. Such changes, called post-translational modifications, can significantly alter a protein's function or fate.

Weissman, Khanna, and colleagues started with a protein known as gp78, which tags specific proteins with ubiquitin. Ubiquitylation can lead to the destruction of tagged proteins by a complex cellular machine called the proteasome. Cells use ubiquitylation as a means to regulate the levels of critical proteins within the cells as well as to remove unnecessary and damaged proteins.

By silencing the activity of gp78, the NCI team found that the spread and survival of cancer cells in animal models was greatly reduced. The researchers also discovered that gp78 interacts with another protein called KAI1, a protein which has previously been shown to interfere with metastasis and is categorized as a metastasis suppressor. In the model the researchers used, silencing gp78 in sarcoma cells caused levels of KAI1 to rise, and decreased cancer cell survival. Conversely, in sarcoma cells with high levels of gp78, KAI1 was more frequently tagged for destruction. The scientists found that this silencing of KAI1 in cancer cells encouraged both cancer cell survival and metastasis.

Going a step further, the NCI team examined archived sarcoma tumor samples from patients, and found that tumors with low levels of gp78 had higher levels of KAI1, and that tumors with high levels of gp78 had lower levels of KAI1. While the number of sarcomas sampled was relatively small, the result suggests that KAI1 ubiquitylation by gp78 could play a role in cancer spread in human sarcoma. This leads to the question of how ubiquitylation of proteins by gp78 might affect other human cancers.

"This is the first example of how ubiquitylation can impact metastasis by altering the level of a metastasis suppressor" said Weissman. "These findings offer a rationale for the use of current proteasome inhibitors, such as bortezomib, and for the development of drugs that interfere with ubiquitylation to treat metastatic cancers."

Tsai YC, Mendoza A, Mariano JM, Zhou M, Kostova Z, Chen B, Veenstra T, Hewitt SM, Helman LJ, Khanna C, and Weissman AM. December 2007. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med. Vol. 13, No.12.

Researchers are from the Laboratory of Protein Dynamics and Signaling, CCR and the Biomedical Proteomics Program, NCI, Frederick, Md.; the Pediatric Oncology Branch and Tissue Array Research Program, CCR; and the Biomedical Proteomics Program, NCI, U.S. Department of Health and Human Services, Bethesda, Md.

For more information on research in Dr. Weissman's lab, please go to http://ccr.ncifcrf.gov/staff/staff.asp?profileid=6524, and for research in Dr. Khanna's lab, please go to http://ccr.cancer.gov/Staff/Staff.asp?profileid=8295.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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