Lower Levels of Key Protein Influence Tumor Growth in Mice, Stanford Study Shows

STANFORD, Calif.--(Business Wire)--
Tumors need a healthy supply of blood to grow and spread. Researchers at the
Stanford University School of Medicine have identified a molecule that regulates
blood vessel growth that is often found at less-than-normal levels in human
tumors. Blocking the expression of the molecule, called PHD2, allows human
cancer cells to grow more quickly when implanted into mice and increases the
number of blood vessels feeding the tumor.

"It appears to be acting as a tumor suppressor by negatively controlling blood
vessel formation," said cancer biologist Amato Giaccia, PhD, the Jack, Lulu and
Sam Willson Professor and professor of radiation oncology. He and his colleagues
are hopeful that targeting the downstream molecules activated when PHD2 levels
are low may be an effective treatment for a variety of human cancers.

Giaccia is the senior author of the research, which will be published in the
June 2 issue of the journal Cancer Cell. He is also a member of Stanford`s
Cancer Center.

The finding was particularly surprising because PHD2 was already known to play a
less-direct role in blood vessel formation: that of destabilizing another
important cancer-associated protein, HIF-1. HIF-1, which stimulates blood vessel
development, is induced by the low oxygen levels found in many solid tumors.
Although the HIF-1 molecule is rarely modified in human cancers, its levels are
often elevated as compared to normal tissue. Giaccia and his colleagues wondered
if the higher levels of HIF-1 could be explained by decreases in the level of
PHD2.

The researchers measured PHD2 levels in several human tumor samples, including
breast and colon cancers, and compared them with surrounding tissue. They found
that, in many cancers, the tumors did have lower-than-normal levels of PHD2.
They then inhibited the expression of PHD2 in a variety of human cancer cells in
the lab, transplanted these cells into mice with compromised immune systems and
examined the tumors that resulted. Those arising from cells in which PHD2
expression had been blocked grew more quickly and were more highly vascularized
than the unmodified control cells.

Surprisingly, however, these effects of PHD2 inhibition were evident even in
cells engineered not to express HIF-1. "Nobody expected this," said Giaccia.
"It`s always been thought that the major role of PHD2 was in regulating HIF-1
activity. But now we`ve learned that it seems to control tumor growth through
blood vessel formation in a variety of different cell types on its own."

Upon further investigation, the researchers learned that blocking PHD2
expression increases the levels of two other important proteins involved in
vessel formation: IL-8 and angiogenin. The researchers believe that blocking the
activity of these proteins may be a good way to stunt tumor growth. "Prior to
this study," said Giaccia, "it was unclear which of the many proteins involved
in vessel growth, or angiogenesis, should be targeted. But now we know they play
a predominant role in tumor growth."

He and his colleagues are planning to continue their studies in laboratory mice
engineered to develop breast cancer. They will investigate whether a version of
the mice lacking PHD2 expression develops more aggressive tumors, and whether
blocking IL-8 or angiogenin slows tumor growth.

In addition to Giaccia, other Stanford researchers involved in the work include
postdoctoral scholar Denise Chan, PhD; graduate student Tiara Kawahara; and
associate professor of dermatology Howard Chang, MD, PhD. The study was funded
by a Silicon Valley Community Fellowship, the National Cancer Institute and the
National Institutes of Health.

The Stanford University School of Medicine consistently ranks among the nation`s
top 10 medical schools, integrating research, medical education, patient care
and community service. For more news about the school, please visit
http://mednews.stanford.edu. The medical school is part of Stanford Medicine,
which includes Stanford Hospital & Clinics and Lucile Packard Children`s
Hospital. For information about all three, please visit
http://stanfordmedicine.org/about/news.html.

Stanford University School of Medicine
Print Media:
Krista Conger, 650-725-5371
kristac@stanford.edu
Broadcast Media:
M.A. Malone, 650-723-6912
mamalone@stanford.edu

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