Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Conversion of brain tumor cells into blood vessels thwarts treatment efforts

Glioblastoma, the most common and lethal form of brain cancer and the disease that killed Massachusetts Senator Ted Kennedy, resists nearly all treatment efforts, even when attacked simultaneously on several fronts. One explanation can be found in the tumor cells' unexpected flexibility, discovered researchers at the Salk Institute for Biological Studies.

When faced with a life-threatening oxygen shortage, glioblastoma cells can shift gears and morph into blood vessels to ensure the continued supply of nutrients, reports a team led by Inder Verma, Ph.D., in a feature article in this week's issue of the Proceedings of the National Academy of Sciences.

Their study not only explains why cancer treatments that target angiogenesis--the growth of a network of blood vessels that supplies nutrients and oxygen to cancerous tissues--routinely fail in glioblastoma, but the findings may also spur the development of drugs aimed at novel targets.

"This surprising effect of anti-angiogenic therapy with drugs such as Avastin tells us that we have to rethink glioblastoma combination therapy," says senior author Verma, a professor in the Laboratory of Genetics and holder of the Irwin and Joan Jacobs Chair in Exemplary Life Science. "Disrupting the formation of tumor blood vessels is not enough; we also have to prevent the conversion of tumor cells into blood vessels cells."

To grow beyond one to two millimeters in diameter--roughly the size of a pinhead--tumors need their own independent blood supply. To recruit new vasculature from existing blood vessels, many tumors overexpress growth factors, predominantly vascular endothelial growth factor, or VEGF. This led to the development of Avastin, a monoclonal antibody that intercepts VEGF.

"In a recent phase II clinical trial, 60 percent of patients with glioblastoma responded to a combination of Avastin and Irinotecan, which directly interferes with the growth of cancer cells," explains Verma, "but in most patients this effect was only transient." In fact, studies have shown that tumor cells often become more aggressive after anti-angiogenic therapy, but the reason had been unclear.

To find out, postdoctoral researcher and first author Yasushi Soda, Ph.D., took advantage of a mouse model of glioblastoma that recapitulates the development and progression of human brain tumors that arise naturally. "The tumors in these mice closely resemble glioblastomas, including the typically messy and highly permeable tumor vessels, which allowed us to study the tumor vasculature in great detail," he explains.

The glioblastoma mice, the concept for which was developed in the Verma laboratory, grow brain tumors within a few months of being injected with viruses that carry activated oncogenes and a marker gene that causes all tumor-derived cells to glow green under ultraviolet light. By simply tracking the green glow under the microscope, the Salk researchers can then follow the fate of tumor cells.

When Soda peered at the tumor cells, he found--much to his surprise--that about 30 percent of vascular endothelial cells--specialized cells that line the interior surface of blood vessels--appeared green. "This indicated to us that they most likely originated from tumor cells," he says.

Further experiments revealed that TDECs, short for tumor-derived endothelial cells, are not specific to mouse tumors but can also be found in clinical samples taken from human glioblastoma patients. "This was really strong evidence for us that glioblastoma cells routinely transdifferentiate into endothelial cells," he explains.

The transformation is triggered by hypoxia, or low oxygen levels, which signals tumor cells that the time has come to start their shape-shifting stunt. But unlike regular vascular endothelial cells, TDECs don't require VEGF to form functional blood vessels. "This might explain why, despite being initially successful, anti-angiogenic therapy ultimately fails in glioblastomas," says Verma.

Avastin interrupts normal blood vessels, but eventually they are replaced with tumor-derived vessels, which are now treatment-resistant. "Once again, we are confronted with the versatility of tumor cells, which allows them to survive and thrive under adverse conditions," says Verma. "But as we learn more about tumors' molecular flexibility, we will be able to design novel, tailor-made combination therapies to combat deadly brain tumors."

Researchers who also contributed to the work include Tomotoshi Marumoto, Dinorah Friedmann-Morvinski, Mie Soda, and Fei Liu at the Salk Institute; Hiroyuki Michiue in the Department of Physiology at the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Sandra Pastorino and Santosh Kesari in the Department of Neurosciences, Moore's Cancer Center, at the University of California, San Diego; as well as Meng Yang and Robert M. Hoffmann at AntiCancer, Inc., San Diego.

The work was funded in part by the National Institutes of Health, the Merieux Foundation, the Ellison Medical Foundation, Ipsen/Biomeasure, Sanofi Aventis, the H.N. and Frances C. Berger Foundation, and the James S. McDonnell Foundation.

About the Salk Institute for Biological Studies:

The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

Gina Kirchweger | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Advanced analysis of brain structure shape may track progression to Alzheimer's disease
26.10.2016 | Massachusetts General Hospital

nachricht Indian roadside refuse fires produce toxic rainbow
26.10.2016 | Duke University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

'Neighbor maps' reveal the genome's 3-D shape

27.10.2016 | Life Sciences

Gene therapy shows promise for treating Niemann-Pick disease type C1

27.10.2016 | Life Sciences

Solid progress in carbon capture

27.10.2016 | Power and Electrical Engineering

More VideoLinks >>>