High TIMP-1 Levels May Promote Prostate Cancer Growth

SAN FRANCISCO—High levels of a protein that normally prevents tumor growth may actually encourage angiogenesis and the spread of prostate cancer, according to a poster presented at the 40^th Annual Meeting of the American Society for Cell Biology.

Overexpression of the TIMP-1 protein (tissue inhibitor of metalloprotein-ases) may help explain why the mortality rate from prostate cancer is higher among black men than white men.

"Usually the TIMP-1 protein inhibits metalloproteinase, but when it is elevated, it fails to keep the enzyme in check," said Briana Jill Williams, PhD, lead researcher and director of Basic Urologic Research, Louisiana State University Health Sciences Center, Shreveport. Metalloproteinase is secreted from tumors, dissolves surrounding tissue, and gives the tumors more room to grow.

"In the prostate tumor tissues from African-American men, TIMP-1 was highly elevated, compared with levels in tumor tissues from white men, suggesting to us that an imbalance in TIMP-1 can change its role from inhibiting to promoting tumor growth," she said.

The researchers looked at prostate tumor tissues from 100 men, half of them black. They noticed that there was a higher microvessel density around the black men’s tumors, suggesting there was more angiogenesis. Yet TIMP-1, which normally stops the process of tumor invasion, was also elevated.

When they searched the literature for the reasons, they found that elevated TIMP-1 has been associated with poor cancer prognosis in studies of breast and colon cancers. The literature also seemed to indicate it has some growth factor properties.

In laboratory tests, the researchers then discovered that overproduction of TIMP-1 boosted the levels of vascular endothelial growth factor (VEGF), the most effective known stimulant of new blood vessel formation. It also increased the rate of migration of cells through an artificial membrane that mimics the extracellular matrix around cells, including blood vessels and the tumor cells.

The researchers’ conclusions were substantiated when they showed that high levels of TIMP-1 changed the morphology of cells, including increased multinu-cleation, increased chromosome number, incomplete cytokinesis bridge formation, and increased cell polarity.

Overexpression of TIMP-1 was also associated with other changes in gene expression, especially increases in several proteins in the ras family, a proto-oncogene that controls cell shape and movement.

The researchers thus concluded that an abnormally high amount of TIMP-1 changes its function and promotes cell growth, motility, and invasion properties in the tumors of black men.

The next step is to test whether high TIMP-1 levels do indeed create more aggressive metastatic tumors. They hope to answer this question by studying human tumor tissue samples from black men with prostate cancer and correlating TIMP-1 levels with outcomes. "We don’t know if our prediction will hold true," she said. They also plan to model overexpression of TIMP-1 in animals.

"To truly understand why elevated TIMP-1 creates tumor growth and metastasis, we may have to go after the things upstream, as well as downstream, of TIMP," Dr. Williams said. Understanding and detailing the genetic pathways that create TIMP overexpression may reveal how to target future medications.

"The cause of TIMP overexpression may be genetic, but it could also be dietary or environmental. We have yet to find the reason," Dr. Williams said.