"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.PRINT MEDIA CONTACT: Krista Conger at (650) 725-5371 (email@example.com)
Krista Conger | EurekAlert!
Study relating to materials testing Detecting damages in non-magnetic steel through magnetism
23.07.2018 | Technische Universität Kaiserslautern
Innovative genetic tests for children with developmental disorders and epilepsy
11.07.2018 | Christian-Albrechts-Universität zu Kiel
There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.
The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
21.08.2018 | Power and Electrical Engineering
21.08.2018 | Life Sciences
21.08.2018 | Medical Engineering