SAN FRANCISCOHigh 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 40th 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
"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.