Prostate cancer is the second most common cause of cancer-related death among men in the United States. Most of the deaths are the result of tumor metastases rather than the primary tumor, yet metastasis remains one of the least understood aspects of the disease. A previous study found that RKIP (Raf kinase inhibitor protein) was expressed at lower levels in metastatic prostate cancer cells than in primary prostate cancer cells, suggesting that RKIP may be a suppressor of prostate cancer metastasis.
Zheng Fu, Ph.D., and Evan T. Keller, D.V.M., Ph.D., of the University of Michigan, Ann Arbor, and their colleagues compared levels of RKIP expression in non-metastatic prostate cancer cell lines and metastatic prostate cancer cell lines. They found that the metastatic cells had four- to fivefold less RKIP mRNA and approximately threefold less RKIP protein than primary prostate cancer cells. They also looked at RKIP expression in human normal and cancerous prostate tissue samples. RKIP was found in all noncancerous prostate tissue and primary prostate cancers examined but was absent in all prostate cancer metastases examined.
The researchers then engineered metastatic prostate cancer cells to express higher levels of RKIP. They found that increased RKIP expression had no effect on proliferation or colony-forming abilities of cultured cells--two factors associated with tumorigenicity. However, increased RKIP expression was associated with a 48.5% decrease in the invasiveness of the cells.
Moreover, increased RKIP expression appeared to reduce the number of lung metastases in mice. For example, mice injected with metastatic cancer cells with increased RKIP expression had 85% fewer lung metastases than mice injected with metastatic cancer cells with normal RKIP expression. Increased RKIP expression was also associated with decreased vascular invasion and decreased ability to form new tumor-nourishing blood vessels.
"Our data suggest that decreased expression of RKIP promotes metastasis through several different complementary mechanisms that altogether confer the ability of vascular invasion on prostate cancer cells," the authors write. "These mechanisms include both increased invasive potential and promotion of angiogenesis in the tumor tissue, resulting in an increased number of blood vessels available for invasion."
In an accompanying editorial, Danny R. Welch, Ph.D., of the University of Alabama at Birmingham, and Kent W. Hunter of the National Cancer Institute, point out that the ability to inhibit prostate cancer metastasis without suppressing tumorigenicity is a characteristic of metastasis suppressors. They say that RKIP is the thirteenth in a growing number of known metastasis suppressor genes and that these genes represent new targets for cancer control.
"The fact that some of the known metastasis suppressors can now be arranged into pathways … signals a major step toward controlling the most deadly attribute of cancer cells," they conclude.
Contact: Kara Gavin, University of Michigan, 734-764-2220; fax: 734-615-2169, kegavin@umich.edu .
Editorial: Laura Mansfield, University of Alabama at Birmingham, 205-934-3889; fax: 205-975-6147, lam@uab.edu.
Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, et al. Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 2003;95:878–89.
Editorial: Welch DR, Hunter KW. A new member of the growing family of metastasis suppressors identified in prostate cancer. J Natl Cancer Inst 2003;95:839–41.
Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage.
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JNCI Journal of the National Cancer Institute