Subversive Role for Cancer Inhibitor?

African-American men's risk of prostate cancer is three times higher than that of Caucasians. Once diagnosed, they also have double or triple the mortality rate. Now, a team of researchers has found a surprising twist: Prostate tumors in African-Americans tend to have much higher levels of a protein that is best known for helping to prevent cancer cells from spreading. The researchers suggest that the compound may turn out to be a useful marker for indicating which men need to have their cancers closely monitored.

Scientists first thought that the higher prostate cancer risk and poorer prognosis for black men were due to socioeconomic factors, such as late diagnoses. Studies have disproved that idea, leaving researchers searching for alternative explanations. Briana Williams, a molecular biologist at the Louisiana State University Health Sciences Center in Shreveport, and her colleagues decided to look for biological differences in 100 prostate tumors, matched for disease stage and other clinical factors. They found that African-Americans had a much higher density of microscopic blood vessels feeding the tumor. This finding suggested that the growth of new vessels--a process called angiogenesis--occurred at a faster pace.

Following this hunch, the team took 20 tumors from both black and white men, and analyzed the genes thought to be involved in angiogenesis or metastasis. Ten genes were expressed at least three times more in tumor tissue from black men. One of these, called TIMP-1, was expressed 24 times more, Williams reported earlier this month at the American Society for Cell Biology meeting in San Francisco. But, strangely, TIMP-1 inhibits metalloproteinases, enzymes involved in breaking down extracellular matrix and prompting cancer cells to spread and invade other tissues. So, normally, TIMP-1 should help prevent cancer progression or invasion. Although cancerous prostate tissue from black men had, on average, higher levels of TIMP1 than that of white men, their metalloproteinase levels were not excessively elevated.

Intrigued, Williams and her colleagues engineered a line of human cancer cells to express high levels of TIMP-1. When they examined these cells, they found high levels of VEGF, a growth factor known to stimulate angiogenesis. Apparently, a greatly increased TIMP-1 production does not inhibit metalloproteinases, says Williams, but it does lead to higher VEGF levels, which in turn stimulate blood vessel growth. Her team is now testing this idea in rodents, and the researchers plan to examine more samples of prostate cancer as well.

The finding is "novel and potentially interesting," says Lynn Matrisian, a cancer biologist at Vanderbilt University in Nashville who studies matrix-degrading metalloproteinases--but she's not buying it yet. The study goes against the "dogma" that TIMP-1 production protects from cancer, she says. "They would need more studies that suggest a mechanism before this would make sense to me."

William cautions that even though high TIMP-1 levels may eventually be found to predict aggressive prostate cancers, they may not be the ultimate cause of metastasis. She and her colleagues are studying genetic and environmental factors that control TIMP-1 levels, such as cholesterol--which tends to be higher in African-Americans.

Related sites

Information on prostate cancer, from the National Cancer Institute

Briana William's abstract

Lynn Matrisian's home page, with information on metalloproteinases