Cancer cells forming blood vessels send their copper to the edge
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ARGONNE, Ill. (Feb. 26, 2007) — New information about a link between
the growth of blood vessels critical to the spread of cancer and the copper
in our bodies has been discovered by researchers from the U.S. Department
of Energy's Argonne National Laboratory and the University of Chicago, using
a beamline at the Advanced Photon Source.
Growing new blood vessels from existing ones — a process called angiogenesis — is
important in growth, development and wound healing. But it also enables the
spread of tumors throughout the body, so researchers have been scrambling for
ways to stop angiogenesis in the fight against cancer.
One element critical to blood vessel growth is copper, a vital nutrient that
plays important roles in many life processes. Compounds that reduce copper
in the body without disrupting the body's normal functions can inhibit the
growth of blood vessels — and some of these compounds are even in clinical
trials for use in cancer therapy. Yet, the biological basis for this sensitivity
of angiogenesis to copper has been an enigma.
In search of an answer, researchers from the Biosciences and X-ray
Science divisions at Argonne and the Department
of Medicine, Section of Hematology/Oncology,
at the University of Chicago, have used X-ray fluorescence microprobe imaging
at the Advanced Photon Source at Argonne, the Western Hemisphere's most brilliant
source of X-rays for research. The X-rays allowed the researchers to look at
the distribution of copper in both a cell model of angiogenesis and sections
of breast tumor tissue rich in blood vessels.
“We found that cells undergoing angiogenesis exhibit a distribution of their
cellular copper that is distinctly different from other cells,” said Argonne
biologist and lead author Lydia Finney. “This discovery may help explain how
copper-reducing cancer therapy works.” The findings are reported in the current
issue of the Proceedings
of the National Academy of Sciences, or PNAS.
“We began our study,” Finney explained, “ by examining a model of angiogenesis
that uses human microvascular endothelial cells to form capillary-like structures
within about eight hours of being stimulated with specific growth factors.
We then examined the distribution of elements in these structures by using
imaging resources.”
The APS played a key role in the research. The particular APS beamline Finney
and her colleagues used employs specialized optics to focus coherent X-rays
to sub-micrometer spot sizes, through which the sample is raster scanned (scanning
from side to side, top to bottom). By collecting emitted fluorescence spectra
at each point using an energy-dispersive detector, the researchers obtained
images displaying the concentration and spatial distribution of many elements,
including phosphorous, sulfur, iron, copper and zinc. Overlaying these elemental
maps onto optical images of the cells, Finney and her colleagues then correlated
elemental content with cellular structures.
“Our findings were very clear,” said Finney. “We observed a dramatic relocalization
of between 80 and 90 percent of cellular copper to the tips of the tendril-like
projections angiogenic cells send out between one another and across the cellular
membrane within the first two hours.” Copper did, indeed, appear to play a
special role in angiogenesis, at least on the basis of this observation.
To extend these studies to a living organism, Finney and her colleagues then
examined sections of breast tumor tissue that were rich in newly formed blood
vessels. “Once again,” said Finney, “we found that in contrast to both non-vascularized
areas and areas of mature blood vessels, in areas of tissue where blood vessels
were newly invading surrounding tissue, the cells showed copper localized at
the periphery of the cells and in areas immediately outside of any apparent
cellular structures.”
What are the implications of this discovery?
According to Finney, “These findings improve our understanding of how removing
copper from the body can help stop angiogenesis. If a drug can be used to intercept
vital copper being translocated outside of the cell during angiogenesis, the
process stops, preventing growth of the tumor.”
The implications of the research do not end with the effect on angiogenesis.
The dynamics of cellular copper this study revealed also have broad implications
on the regulation of the metal ion content in metal-binding proteins. If such
dramatic changes in where cellular copper is stored and used can happen so
rapidly during angiogenesis, then the interactions of metal ions, such as copper,
with the proteins and macromolecules that bind them in the cell must have very
fluid dynamics themselves.
Other authors on the study are Suneeta Mandava, Lyann Ursos, Wen Zhang, Diane
Rodi, Stefan Vogt, Daniel Legnini, Jörg Maser and David Glesne of Argonne
and Francis Ikpatt and Olufunmilayo I. Olopade of the University of Chicago.
The research, and use of the Advanced Photon Source, were supported by the
U. S. Department of Energy, Office of Science. — Kevin Brown
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For more information, please
contact Eleanor Taylor (630/252-5510 or media@anl.gov)
at Argonne.
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