Prostate cancer doesn't kill its victims. It's the metastasis that does the lethal work.

Annually, 35,000 to 40,000 American men die of the malignancy. Another 200,000 prostate cancer (PC) patients are diagnosed with the disease each year, which is the second-leading cause of neoplastic deaths among U.S. males. PC is a slow-growing malady, which strikes relatively late in life. In fact, many, if not most, patients are less likely to succumb to PC than to other casualties of old age.

PC has a highly erratic behavior. Some of its patients are fated to hit the fatal road to metastasis; others might lie low until felled by some other unsuspected ill or accident. "PC is a very slow-growing tumor," observed molecular endocrinologist Evan Keller at the University of Michigan School of Medicine in Ann Arbor. "Some men may not have accumulated all the necessary molecular steps - but they have eaten." Keller explained: "Where diet plays a significant role, environmental factors may associate with PC. Some men with higher body mass - actually associated with abdominal girth - have a higher likelihood of developing prostate cancer."

Keller cited another social factor that accounts for being prone to metastasis or exempt from that specificity. "There's racial makeup," he offered. "African-Americans have a higher incidence of PC, whereas Asian men have a much lower probability. We don't know the scientific reason but suggestions would again be under primary dietary influences," Keller observed. His research focuses on PC metastasis, and he is an associate professor of comparative medicine and pathology at the university. He also is senior author of an article in the twice-monthly Journal of the National Cancer Institute, dated June 18, 2003. Its title: "Effects of Raf Kinase Inhibitor Protein: Suppression of Prostate Cancer Metastasis."

"Our main finding," Keller observed, "is that we have identified a protein, which when downregulated, or expressed at lower levels in prostate cancer, enhances the ability of its tumor cells to metastasize specifically by invading the blood vessels. These then serve as superhighways to the rest of the body. This is the first time a molecule has been shown that inhibits downregulation in cancer and control over clinical metastasis. So it really makes a potentially viable therapeutic target."

RKIP Protein Frustrates Tumor Urge To Metastasize

The protein Keller and his team discovered some three and a half years ago is called RKIP, standing for "Raf kinase inhibitor protein." It governs the ability of PC cells to leave their original lodgings and penetrate nearby blood vessels. Such vascular invasion is the first step in a cascade of events leading to metastasis, the cancer's deadly spread throughout the body. "The gene encoding RKIP appears to be a novel metastasis-suppressor gene," Keller noted. "It's involved in blocking the cell signaling processes that allow cancer cells to enter the bloodstream.

"Lung, liver, brain and bone are probably the big advanced metastatic targets," Keller said. "When PC spreads to the bone," he continued, "it can be a matter of months before the patient will die from it. But it may happen very quickly. Once it breaks into the blood vessels, the grace period to death can be very short. We think the ultimate demise or failure is what we call cachexia - wasting away - because the tumor burden has become so large their body has just stopped functioning appropriately.

"We consider the metastatic process a very complex cascade, where the cells have to attach to the primary tumor entering into the blood vessel and travel through the blood stream. Avoiding the immune system, which may be trying to kill these bad cells, they have to attach to the secondary metastatic site - the lung or the liver - and then it has to express out of the blood vessel into the tissue, where it has to invade blood vessels and set up tumor growth again.

"We started by confirming our initial finding of decreased RKIP in metastatic cancer cells," Keller related. "We obtained these 25 tumor samples from a very special program we have here called Rapid Autopsy Program. These are men who come here with terminal prostate cancer and were willing when they died to let us do an autopsy within hours of their death. We have a very specialized team here to explore these questions. So when they did die within hours, we had a full autopsy of samples throughout their body. We put those tissue and cell specimens on microarray chips. We can have 100 samples from different people and different tissues, which we stain with antibodies of RKIP, so all the tissues are getting the same treatment with no variability between specimens."

Postmortem Tumor Gifts: A Wonderful Resource'

"This has been a wonderful resource in doing fresh, human PC samples so that we can look at a variety of tissues and metastases within the same person. It gives us a very good clue to the biology of prostate cancer itself, which helps eventually to identify potential therapeutic targets. We believe our postmortem lab findings are especially relevant to real-life cases of cancer. Used nationally, people will come to us for this resource and ask for these samples.

"In our ongoing research," Keller recounted, "we're asking: Does this have a role in other cancers? Is it a global phenomenon, or limited to the prostate?' In looking at tissues from other malignancies, we're focusing on breast, colon and the really big ones. We're also looking at tissues from PC men to see if early indication of RKIP in the actual biopsies may help predict whether they're going to develop metastases and whether there might be more aggressive therapy.

"Based on this work," he added, "one might hypothesize or suggest that we could potentially construct a human gene therapy approach, where we could take vectors that would target prostate and overexpress RKIP for example, to avoid the metastatic process. That of course," Keller concluded, "would be quite some time away."

The journal paper summed up: "The growing numbers of metastasis suppressor genes represent new targets for cancer control. The same way that RKIP involvement signals a major step toward controlling the most deadly attribute of cancer cells."