Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Inflammatory protein converts glioblastoma cells into most aggressive version

30.08.2013
Conditions in brain tumor environment trigger previously unexplained cellular transition and radiation resistance

A prominent protein activated by inflammation is the key instigator that converts glioblastoma multiforme cells to their most aggressive, untreatable form and promotes resistance to radiation therapy, an international team lead by researchers at The University of Texas MD Anderson Cancer Center reported online today in the journal Cancer Cell.

The discovery by scientists and physicians points to new ways to increase radiation effectiveness and potentially block or reverse progression of glioblastoma multiforme, the most common and lethal form of brain tumor.

"We know that the mesenchymal (MES) subgroup of glioblastoma cells is the most aggressive subgroup clinically," said co-senior author Ken Aldape, M.D., chair and professor of Pathology and Kenneth D. Muller Professor in Tumor Genetics. "This paper shows that the NF-kB pathway causes cells to change to that MES subgroup."

This conversion leads to radiation resistance.

"The pathway we identified serves as an escape mechanism for tumors," said lead author Krishna Bhat, Ph.D., assistant professor of Pathology. "In newly diagnosed patients, even before treatment, these cells already are poised to meet radiation therapy challenges."

NF-êB-driven cell change starts outside the tumor

NF-êB activation is stimulated by inflammation, which occurs in the tumor cell's microenvironment.

"The shift of tumor cells to a MES type, characterized gene expression associated with invasion and new blood vessel formation, leads to radiation resistance," said co-senior author Erik Sulman, M.D., Ph.D., assistant professor of Radiation Oncology. "This suggests blocking the inflammatory response to make tumors more sensitive to standard radiation treatment may improve outcomes for patients."

Standard care for glioblastoma is surgery, followed by radiation and chemotherapy and then treatment with temozolomide. An estimated 23,270 people will receive a glioblastoma diagnosis in 2013 and about 14,000 people will die of the disease. Median survival is about one year.

Cell line, mouse model show something missing

"No one really knows how glioblastoma progresses from its early stages because 90-95 percent of cases are diagnosed without prior history of a lower grade glioma," Bhat said. Of these about 50 percent belong to the MES subgroup. A previous study had shown that glioblastomas with a proneural (PN) type, have a much better prognosis. But these less-aggressive tumors tend to recur as the aggressive MES subtype after treatment."

Research at MD Anderson and other institutions identified the two distinct cell types based on genes expressed by each. "We haven't known what makes a cell evolve into the MES subtype," Bhat said.

Bhat took cells from 41 human glioblastoma samples and placed them in cell cultures. Of these, 33 developed into neurospheres, cells that take on stem-cell like characteristics.

Microarray analysis of gene expression in the 17 fastest -expanding cell cultures divided them into two distinct groups: one cluster similar to the MES subtype and the other the PN subtype.

They analyzed expression of four genes commonly expressed by each subtype to see how the cultured cells matched up to their parental tumors.

Cue the surprise

All but two of the cell lines (70 percent) that originated from MES tumors lost their MES characteristics and acquired a PN signature. These results do not match the human experience, Bhat noted. Glioblastoma cells don't retreat from an aggressive to less aggressive state.

Either something in the cell culture system favored enrichment of the PN state, or most glioblastoma neurospheres exist in the less-aggressive PN state, and something in the tumor microenvironment triggers their reversible differentiation into the MES state.

Placing the PN cells cultured from MES tumors in mice did not restore those cells to the parent tumor's more aggressive type.

Different responses to radiation treatment

The researchers implanted glioblastoma sphere culture grafts from MES and PN types in mice and then treated them with radiation.

Those with the PN type had increased survival after treatment compared to controls and had a dramatic accumulation of cells (48 to 78 percent) stuck in a specific phase of the cell cycle caused by irradiation, which lead to massive cell death.

Irradiating MES tumors produced no or minimal survival advantage and the percentages of cells arrested by treatment was reduced to 19-25 percent. The MES cells also showed an enhanced ability to repair damage caused by irradiation.

The Cancer Genome Atlas project for glioblastoma had previously found that genes in the TNFá receptor family and the NF-êB pathway are enriched in MES subclass tumors that also express high levels of the surface receptor CD44.

This team found the exact same pathway had been turned on in the MES cells in their study.

Subsequent experiments found:

Treating PN cells with TNFá caused a dramatic increase in CD44 expression. This effect could be reversed by impeding NF-êB.
Pretreating PN cells with TNF-alpha before radiation treatment greatly reduced cell damage.

NF-êB controls three main transcription factors known to produce the MES cell signature and forces conversion to MES by inducing those factors.

MES cells, CD44 levels, NF-kB activation predict human radiation response

In a cohort of newly diagnosed glioblastoma patients, the team found that those in the MES subgroup, with high levels of CD44 and activated NF-êB had poorer response to radiation and reduced survival.

A separate analysis of PN to MES transition in human tumors showed that regions with higher MES signatures had greater invasion by immune cells called macrophages /microglia – elements of the glioblastoma microenvironment – than did PN areas.

"We know we have to control inflammation in this disease," Bhat said. NF-êB is known to play an important role in promoting inflammation in multiple cell types.

"Surprisingly we found that activation of NF-êB was prevalent in the MES subtype even before surgery and radiation, which in turn can cause inflammation and further activation of NF-êB."

Bhat is investigating downstream targets of NF-êB that promote radiation resistance in glioblastoma.

Inhibitors of NF-êB are in clinical trials for inflammatory and autoimmune diseases, Aldape noted.

"One can imagine a clinical trial in which patients are evaluated for MES status and given an NF-êB inhibitor if they have the MES subtype. You can look at improving radiation response, and also whether you can reverse the MES subtype," Aldape said.

Co-authors with Bhat, Aldape and Sulman are Karlijn Hummelink, Faith Hollingsworth, Khalida Wani, Ph.D., Lindsey Heathcock, Johanna James, Lihong Long and Adriana Olar, M.D., all of the Department of Pathology; co-lead author Ravesanker Ezhilarasan, Ph.D., and Lindsey Goodman, of Radiation Oncology; Suzhen Wang of Neuro-Oncology; Joy Gumin, Ganesh Rao, M.D., Amy Heimberger, M.D., and Frederick Lang, M.D., of Neurosurgery; co-lead author Veerakumar Balasubramaniyan, Ph.D., Divya Raj, Ph.D., Hendrikus W.G.M. Boddeke, Ph.D., Siobhan Conroy, and Wilfred Den Dunnen, M.D., Ph.D., of the University Medical Center Groningen, University of Groningen, Netherlands; co-lead author Brian Vaillant, M.D., of Seton Brain and Spine Institute, Austin; Nina Lelic and Daniel Cahill, M.D., Ph.D., Massachusetts General Hospital/Brain Tumor Center, Boston; Yoshinori Kodama, M.D., Osaka National Hospital, National Hospital Organization, Osaka, Japan; Aditya Raghunathan, M.D., Henry Ford Hospital, Detroit; Kaushal Joshi, Christopher Pelloski, M.D., and Ichiro Nakano, M.D., Ph.D., of The Ohio State University, Columbus, Ohio; Se Hoon Kim, M.D., Ph.D., of the Yonsei University College of Medicine, Seoul; Heidi Phillips, Ph.D., of Genentech, South San Francisco, CA; and Howard Colman, M.D., Ph.D., of Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.

This research was funded by the Caroline Ross Endowed Fellowship in Brain Cancer Research, the American Brain Tumor Association Basic Research Fellowship, MD Anderson's Odyssey Special Fellowship, the Brain Tumor Funders' Collaborative, the Dr. Marnie Rose Foundation, the National Brain Tumor Society; the V Foundation, grants from the National Cancer Institute of the National Institutes of Health including MD Anderson's Brain Tumor SPORE grant (P50CA127001 and R01-CA1208113), MD Anderson's NCI Cancer Center Support Grant (P30 CA016672), the Huntsman Cancer Foundation, the Ben and Catherine Ivy Foundation and the Dutch Cancer Society.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Life Sciences:

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

nachricht How protein islands form
15.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

Im Focus: Scientists improve forecast of increasing hazard on Ecuadorian volcano

Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).

The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

New thruster design increases efficiency for future spaceflight

16.08.2017 | Physics and Astronomy

Transporting spin: A graphene and boron nitride heterostructure creates large spin signals

16.08.2017 | Materials Sciences

A new method for the 3-D printing of living tissues

16.08.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>